ES2539859T3 - New condensed aminodihydrotiazine derivative - Google Patents

Abstract

A compound represented by the formula (I): ** Formula ** or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein Ring A 5 is a C6-14 aryl group that may have 1 to 3 substituents selected from the Substituent Group α, a 5- to 6-membered heteroaryl group that may have 1 to 3 substituents selected from the Substituent Group α or a benzo-condensed heterocyclic group of 9 to 10 members that may have 1 to 3 substituents selected from the Substituent Group α, L is a single bond, an oxygen atom, -NRLCO- (in which RL is a hydrogen atom or a C1-6 alkyl group that may have 1 to 3 substituents selected from the Substituent Group α), a group -NRLC C1-6alkyl (in which RL is a hydrogen atom or a C1-6 alkyl group that may have 1 to 3 substituents selected from Substituent Group α), -NRLSO2- (in which RL is an atom of hydrogen or a C1-6 alkyl group that may have 1 to 3 substitutes sources selected from Substituent Group α), a C1-6 alkylene group that may have 1 to 3 substituents selected from Substituent Group α, a C2-6 alkenyl group that may have 1 to 3 substituents selected from Substituent Group α, or a C2-6 alkynylene group which may have 1 to 3 substituents selected from Substituent Group α, Ring B is a C3-8 cycloalkyl group which may have 1 to 3 substituents selected from Substituent Group α, an aryl group of C6-14 which may have 1 to 3 substituents selected from the Substituent Group α, or a 5-10 membered heterocyclic group that may have 1 to 3 substituents selected from the Substituent Group α, X is a single bond or a C1-3 alkylene group which may having 1 to 3 substituents selected from the Substituent Group α, Y is a C1-3 alkylene group which may have 1 to 3 substituents selected from the Substituent Group α or a C2-3 alkenylene group which may have 1 to 3 Substituents selected from Substituent Group α, Z is an oxygen atom, a sulfur atom, a sulfoxide, a sulfone or -NRM- (in which RM is a hydrogen atom, a C1-6 alkyl group which may have 1 to 3 substituents selected from the Substituent Group α, a C3-8 cycloalkyl group which may have 1 to 3 substituents selected from the Substituent Group α, a C1-6 alkylcarbonyl group which may have 1 to 3 substituents selected from the Substituent Group α, a C6-14-aryl carbonyl group which may have 1 to 3 substituents selected from the Substituent Group α, a C 1-6 alkyl sulfonyl group which may have 1 to 3 substituents selected from the Substituent Group α, an aryl group C6-14-sulfonyl which may have 1 to 3 substituents selected from the Substituent Group α, an aryl group of C6-14 that may have 1 to 3 substituents selected from the Substituent Group α, or a heterocyclic group of 5 to 10 members that may have 1 to 3 substitute tes selected from Substituent Group α), R1 and R2 are each independently a hydrogen atom, a C1-6 alkyl group which may have 1 to 3 substituents selected from Substituent Group α, a C1-6 alkylcarbonyl group which can having 1 to 3 substituents selected from the Substituent Group α, a C6-14-aryl carbonyl group which may have 1 to 3 substituents selected from the Substituent Group α, a C1-6 alkyl sulfonyl group which may have 1 to 3 substituents selected from the Group Substituent α, a C6-14-sulfonyl aryl group that may have 1 to 3 substituents selected from the Substituent Group α, a carbocyclic group of C3-8 that may have 1 to 3 substituents selected from the Substituent Group α, or a heterocyclic group of 5 to 10 members that may have 1 to 3 substituents selected from Substituent Group α, and

Description

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DESCRIPTION

New condensed aminodihydrotiazine derivative

Technical field

The present invention relates to a condensed aminodihydrotiazine derivative and its pharmaceutical use. More particularly, the present invention relates to a condensed aminodihydrotiazine derivative that has an amyloid- protein inhibitory effect (hereinafter referred to as A) or an enzyme 1 inhibitor effect of amyloid precursor protein cleavage - beta site (hereinafter referred to as BACE1 or betasecretase), and is effective in treating a neurodegenerative disease caused by the A protein, in particular Alzheimer's dementia, Down syndrome or the like, and a pharmaceutical composition comprising as active ingredient the condensed aminodihydrotiazine derivative.

Prior art

Alzheimer's disease is a disease characterized by degeneration and loss of neurons as well as by the formation of senile plaques and neurofibrillar entanglements. Currently, Alzheimer's type dementia is only treated with symptomatic treatment using an agent that improves symptoms typified by an acetylcholinesterase inhibitor, and a fundamental remedy to inhibit disease progression has not yet been developed. It is necessary to develop a method to control the cause of the onset of the pathology in order to create a fundamental remedy for Alzheimer's dementia.

It is assumed that the A proteins as metabolites of amyloid precursor proteins (hereinafter referred to as APP) are very involved in the degeneration and loss of neurons and in the onset of dementia symptoms (see documents 3 and 4 not of patents , for example). The A proteins have, as main components, A40, which consists of 40 amino acids, and A42, with two amino acids added to the term

C. It is known that A40 and A42 have a high aggregation capacity (see document 5 non-patent, for example), and are major components of senile plates (see documents 5, 6 and 7 non-patent, for example). Furthermore, it is known that A40 and A42 are increased by mutation of the APP and presenilin genes, which is observed in familial Alzheimer's disease (see non-patent documents 8, 9 and 10, for example). Consequently, a compound that reduces the production of A40 and A42 as a progression inhibitor or prophylactic agent for Alzheimer's dementia is expected.

A is produced by cleaving APP by beta-secretase (BACE1) and subsequently by gamma-secretase. For this reason, attempts have been made to create gamma-secretase and beta-secretase inhibitors to inhibit the production of A. The known beta-secretase inhibitors are disclosed in patent documents 1 to 15 and in non-patent documents 1 and 2, shown below, and the like. In particular, patent documents 1, 14 and 15 describe an aminodihydrotiazine derivative and a compound having BACE1 inhibitory activity.

Prior art documents

Patent documents [Patent Document 1] WO 2007/049532 [Patent Document 2] U.S. Patent No. 3235551 [Patent Document 3] U.S. Patent No. 3227713 [Patent document 4] JP-A-09-067355 [Patent document 5] WO 01/087293 [Patent document 6] WO 04/014843 [Patent document 7] JP-A-2004-149429 [Document Patent No. 8] WO 02/96897 [Patent Document 9] WO 04/043916 [Patent Document 10] WO 2005/058311 [Patent Document 11] WO 2005/097767 [Patent Document 12] WO 2006/041404

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[Patent document 13] WO 2006/041405 [Patent document 14] WO 2008/133273 [Patent document 15] WO 2008/133274

Non-patent documents [Document 1 non-patent] Journal of Heterocyclic Chemistry, Vol. 14, p. 717-723 (1977) [Non-Patent Document 2] Journal of Organic Chemistry, Vol. 33, p. 3126-3132 (1968) [Non-patent document 3] Klein WL, and seven others, Alzheimer’s disease-affected brain: Presence of

oligomeric A ligands (ADDLs) suggests a molecular basis for reversible memory loss, Proceedings of

National Academy of Science USA 2003, Sep 2; 100 (18), p. 10417-10422. [Non-patent document 4] Nitsch RM, and sixteen others, Antibodies against am-amyloid slow cognitive decline in Alzheimer’s disease, Neuron, 2003, May 22; 38, p. 547-554.

[Non-patent document 5] Jarrett JT, and two others, The carboxy terminus of the  amyloid protein is critical for the seeding of amyloid formation: Implications for the pathogenesis of Alzheimers' disease, Biochemistry, 1993, 32 (18), p . 4693-4697.

[Non-patent document 6] Glenner GG, and another, Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein, Biochemical and biophysical research communications, 1984, May 16, 120 (3), p. 885-890.

[Document 7 non-patent] Masters CL, and five others, Amyloid plaque core protein in Alzheimer disease

and Down syndrome, Proceedings of National Academy of Science USA, 1985, June, 82 (12), p. 4245-4249. [Non-patent document 8] Gouras GK, and eleven others, Intraneuronal A42 accumulation in human brain, American Journal of Pathology, 2000, January, 156 (1), p. 15-20.

[Non-patent document 9] Scheuner D, and 20 others, Secreted amyloid protein-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease, Nature Medicine , 1996, August, 2 (8), p. 864-870.

[Non-patent document 10] Forman MS, and four others, Differential effects of the swedish mutant amyloid precursor protein on -amyloid accumulation and secretion in neurons and nonneuronal cells, The Journal of Biological Chemistry, 1997, December 19, 272 ( 51), p. 32247-32253.

SUMMARY OF THE INVENTION Problem to be solved by the invention An object of the present invention is to provide a condensed aminodihydrotiazine compound that differs from

an aminodihydrotiazine derivative and a compound that has an inhibitory activity of BACE1 described in patent document 1, and that has an inhibitory effect on the production of A un or an inhibitory effect of BACE1 and is useful as a therapeutic agent for a neurodegenerative disease caused by A and typified by Alzheimer's type dementia, and its pharmaceutical use.

Means for solving the problem The present invention relates to:

[1] A compound represented by formula (I): [Formula 1]

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image 1

or a pharmaceutically acceptable salt thereof, or a solvate thereof, in which

Ring A is a C6-14 aryl group that may have 1 to 3 substituents selected from the Substituent Group , a 5- to 6-membered heteroaryl group that may have 1 to 3 substituents selected from the Substituent Group  or a benzo heterocyclic group condensed from 9 to 10 members that may have 1 to 3 substituents selected from the Substituent Group ,

L is a single bond, an oxygen atom, -NRLCO- (in which RL is a hydrogen atom or a C1-6 alkyl group which may have 1 to 3 substituents selected from the Substituent Group ), an NRLCO group- C1-6 alkyl (in which RL is a hydrogen atom or a C1-6 alkyl group which may have 1 to 3 substituents selected from Substituent Group ), -NRLSO2- (in which RL is a hydrogen atom or a C1-6 alkyl group which may have 1 to 3 substituents selected from the Substituent Group ), a C1-6 alkylene group which may have 1 to 3 substituents selected from the Substituent Group , a C2-6 alkenyl group which it may have 1 to 3 substituents selected from the Substituent Group , or a C2-6 alkynylene group which may have 1 to 3 substituents selected from the Substituent Group ,

Ring B is a C3-8 cycloalkyl group that may have 1 to 3 substituents selected from the Substituent Group , an aryl group of C6-14 that may have 1 to 3 substituents selected from the Substituent Group , or a heterocyclic group of 5 10 members who can have 1 to 3 substituents selected from the Substituent Group ,

X is a single bond or a C1-3 alkylene group which may have 1 to 3 substituents selected from the Substituent Group ,

Y is a C1-3 alkylene group that may have 1 to 3 substituents selected from the Substituent Group 

or a C2-3 alkenylene group which may have 1 to 3 substituents selected from the Substituent Group ,

Z is an oxygen atom, a sulfur atom, a sulfoxide, a sulfone or -NRM- (in which RM is a hydrogen atom, a C1-6 alkyl group that may have 1 to 3 substituents selected from the Substituent Group , a C3-8 cycloalkyl group that may have 1 to 3 substituents selected from the Substituent Group , a C1-6 alkylcarbonyl group that may have 1 to 3 substituents selected from the Substituent Group , an aryl group C6-14- carbonyl which may have 1 to 3 substituents selected from the Substituent Group , a C1-6-sulfonyl alkyl group which may have 1 to 3 substituents selected from the Substituent Group , a C6-14-sulfonyl aryl group which may have 1 to 3 substituents selected from the Substituent Group , an aryl group of C6-14 that may have 1 to 3 substituents selected from the Substituent Group , or a heterocyclic group of 5 to 10 members that may have 1 to 3 substituents selected from the Substituent Group ),

R1 and R2 are each independently a hydrogen atom, a C1-6 alkyl group that may have 1 to 3 substituents selected from the Substituent Group , a C1-6 alkylcarbonyl group that may have 1 to 3 substituents selected from the Group Substituent , a C6-14-aryl carbonyl group which may have 1 to 3 substituents selected from the Substituent Group , a C1-6 alkyl sulfonyl group which may have 1 to 3 substituents selected from the Substituent Group , a C6-aryl group 14-sulfonyl which may have 1 to 3 substituents selected from the Substituent Group , a C3-8 carbocyclic group that may have 1 to 3 substituents selected from the Substituent Group , or a 5 to 10 membered heterocyclic group that may have 1 to 3 substituents selected from the Substituent Group , and

R3, R4, R5 and R6 are independently a hydrogen atom, a halogen atom, a hydroxy group, a C1-6 alkyl group which may have 1 to 3 substituents selected from the Substituent Group , a C1-6 alkoxy group which may have 1 to 3 substituents selected from the Substituent Group , a carbocyclic group of 3 to 10 members that may have 1 to 3 substituents selected from the Substituent Group , or a heterocyclic group of 5 to 10 members that may have 1 to 3 substituents selected from the Substituent Group , or

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R4 and R6, together, can form a ring represented by formula (II); [Formula 2]

image2

wherein Y, Z, R5 and R3 are as defined above, and Q is an oxygen atom, a methylene group or an ethylene group

[Substituent Group : a hydrogen atom, a halogen atom, a hydroxy group, a nitro group, a C1-6-thio alkyl group, a C6-14 aryl group, a C6-14-oxycarbonyl aryl group, a C6-14-aryl-carbonyl group, a cyano group, a C3-8 cycloalkoxy group, a C3-8 cycloalkyl group, a C3-8-thio cycloalkyl group, a sulfonylamino group (in which the sulfonylamino group may be substituted with 1 to 2 C1-6 alkyl groups), a C2-6 alkenyl group that may have 1 to 2 substituents selected from the Substituent Group , a C2-6 alkynyl group that may have 1 to 2 substituents selected from the Substituent Group , a carbamoyl group that may be substituted with 1 to 2 C1-6 alkyl groups, a C1-6 alkoxy group that may have 1 to 3 substituents selected from the Substituent Group , a C1-6 alkyl group that may have 1 to 3 substituents selected from the Substituent Group , and a 5-10 membered heterocyclic group that can 1 to 3 substituents selected from the Substituent Group ,

Substituent Group : a halogen atom, a cyano group, a hydroxy group and a C1-6 alkoxy group (in which the alkoxy group may be substituted with a phenyl group which may be substituted with 1 to 3 substituents selected from a hydrogen atom, a halogen atom, a hydroxy group and a nitro group]];

[2] A compound represented by the formula (I):

[Formula 3]

image3

or a pharmaceutically acceptable salt thereof, or a solvate thereof, in which

Ring A is a C6-14 aryl group that may have 1 to 3 substituents selected from the Substituent Group , a 5- to 6-membered heteroaryl group that may have 1 to 3 substituents selected from the Substituent Group , or a benzo heterocyclic group - condensate of 9 to 10 members that may have 1 to 3 substituents selected from the Substituent Group ,

L is a single bond, an oxygen atom, -NRLCO- (where RL is a hydrogen atom or a C1-6 alkyl group which may have 1 to 3 substituents selected from the Substituent Group ), -NRLSO2- ( wherein RL is a hydrogen atom or a C1-6 alkyl group that may have 1 to 3 substituents selected from the Substituent Group ), a C1-6 alkylene group that may have 1 to 3 substituents selected from the Substituent Group  , a C2-6 alkenylene group which may have 1 to 3 substituents selected from the Substituent Group , or a C2-6 alkynylene group which may have 1 to 3 substituents selected from the Substituent Group ,

Ring B is a C3-8 cycloalkyl group that may have 1 to 3 substituents selected from the Substituent Group , an aryl group of C6-14 that may have 1 to 3 substituents selected from the Group

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Substituent , or a 5-10 membered heterocyclic group that may have 1 to 3 substituents selected from the Substituent Group ,

X is a single bond or a C1-3 alkylene group which may have 1 to 3 substituents selected from the Substituent Group ,

Y is a C1-3 alkylene group which may have 1 to 3 substituents selected from the Substituent Group ,

or a C2-3 alkenylene group which may have 1 to 3 substituents selected from the Substituent Group ,

Z is an oxygen atom, a sulfur atom, a sulfoxide, a sulfone or -NRM- (in which RM is a hydrogen atom, a C1-6 alkyl group that may have 1 to 3 substituents selected from the Substituent Group , a C3-8 cycloalkyl group that may have 1 to 3 substituents selected from the Substituent Group , a C1-6 alkylcarbonyl group that may have 1 to 3 substituents selected from the Substituent Group , an aryl group C6-14- carbonyl which may have 1 to 3 substituents selected from the Substituent Group , a C1-6-sulfonyl alkyl group which may have 1 to 3 substituents selected from the Substituent Group , a C6-14-sulfonyl aryl group which may have 1 to 3 substituents selected from the Substituent Group , an aryl group of C6-14 that may have 1 to 3 substituents selected from the Substituent Group  or a heterocyclic group of 5 to 10 members that may have 1 to 3 substituents selected from the Substituent Group ),

R1 and R2 are each independently a hydrogen atom, a C1-6 alkyl group that may have 1 to 3 substituents selected from the Substituent Group , a C1-6 alkylcarbonyl group that may have 1 to 3 substituents selected from the Group Substituent , a C6-14-aryl carbonyl group which may have 1 to 3 substituents selected from the Substituent Group , a C1-6 alkyl sulfonyl group which may have 1 to 3 substituents selected from the Substituent Group , a C6-aryl group 14-sulfonyl which may have 1 to 3 substituents selected from the Substituent Group , a C3-8 carbocyclic group that may have 1 to 3 substituents selected from the Substituent Group , or a 5 to 10 membered heterocyclic group that may have 1 to 3 substituents selected from the Substituent Group , and

R3, R4, R5 and R6 are independently a hydrogen atom, a halogen atom, a hydroxy group, a C1-6 alkyl group which may have 1 to 3 substituents selected from the Substituent Group , a C1-6 alkoxy group which may have 1 to 3 substituents selected from the Substituent Group , a carbocyclic group of 3 to 10 members that may have 1 to 3 substituents selected from the Substituent Group , or a heterocyclic group of 5 to 10 members that may have 1 to 3 substituents selected from the Substituent Group , or

R4 and R6, together, can form a ring represented by formula (II):

[Formula 4]

image4

wherein Y, Z, R5 and R3 are as defined above, and Q is an oxygen atom, a methylene group or an ethylene group

[Substituent Group : a hydrogen atom, a halogen atom, a hydroxy group, a nitro group, a C1-6-thio alkyl group, a C6-14 aryl group, a C6-14-oxycarbonyl aryl group, a C6-14-aryl-carbonyl group, a cyano group, a C3-8 cycloalkoxy group, a C3-8 cycloalkyl group, a C3-8-thio cycloalkyl group, a sulfonylamino group (in which the sulfonylamino group may be substituted with 1 to 2 C1-6 alkyl groups), a C2-6 alkenyl group that can have 1 to 2 substituents selected from the group of substituents , a C2-6 alkynyl group that can have 1 to 2 substituents selected from the group of substituents , a carbamoyl group which may be substituted with 1 to 2 C1-6 alkyl groups, a C1-6 alkoxy group which may have 1 to 3 substituents selected from the Substituent Group , a C1-6 alkyl group which may have 1 to 3 substituents selected from the Substituent Group , and a 5-10 membered heterocyclic group that may have 1 to 3 substituents selected from the Substituent Group ,

Substituent Group : a halogen atom, a cyano group, a hydroxy group and a C1-6 alkoxy group];

[3] A compound represented by the formula (I);

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[Formula 5]

image5

or a pharmaceutically acceptable salt thereof, or a solvate thereof, in which

Ring A is a C6-14 aryl group that may have 1 to 3 substituents selected from the Substituent Group , a 5- to 6-membered heteroaryl group that may have 1 to 3 substituents selected from the Substituent Group , or a benzo heterocyclic group - condensate of 9 to 10 members that may have 1 to 3 substituents selected from the Substituent Group ,

L is a single bond, an oxygen atom, -NRLCO- (where RL is a hydrogen atom or a C1-6 alkyl group which may have 1 to 3 substituents selected from the Substituent Group ), -NRLSO2- ( wherein RL is a hydrogen atom or a C1-6 alkyl group that may have 1 to 3 substituents selected from the Substituent Group ), a C1-6 alkylene group that may have 1 to 3 substituents selected from the Substituent Group  , a C2-6 alkenylene group which may have 1 to 3 substituents selected from the Substituent Group , or a C2-6 alkynylene group which may have 1 to 3 substituents selected from the Substituent Group ,

Ring B is a C3-8 cycloalkyl group that may have 1 to 3 substituents selected from the Substituent Group , an aryl group of C6-14 that may have 1 to 3 substituents selected from the Substituent Group , or a heterocyclic group of 5 10 members who can have 1 to 3 substituents selected from the Substituent Group ,

X is a single bond or a C1-3 alkylene group which may have 1 to 3 substituents selected from the Substituent Group ,

Y is a C1-3 alkylene group which may have 1 to 3 substituents selected from the Substituent Group ,

or a C2-3 alkenylene group which may have 1 to 3 substituents selected from the Substituent Group ,

Z is an oxygen atom, a sulfur atom, a sulfoxide, a sulfone or -NRM- (in which RM is a hydrogen atom, a C1-6 alkyl group that may have 1 to 3 substituents selected from the Substituent Group , a C3-8 cycloalkyl group that may have 1 to 3 substituents selected from the Substituent Group , a C1-6 alkylcarbonyl group that may have 1 to 3 substituents selected from the Substituent Group , an aryl group C6-14- carbonyl which may have 1 to 3 substituents selected from the Substituent Group , a C1-6-sulfonyl alkyl group which may have 1 to 3 substituents selected from the Substituent Group , a C6-14-sulfonyl aryl group which may have 1 to 3 substituents selected from the Substituent Group , an aryl group of C6-14 that may have 1 to 3 substituents selected from the Substituent Group , or a heterocyclic group of 5 to 10 members that may have 1 to 3 substituents selected from the Substituent Group ),

R1 and R2 are each independently a hydrogen atom, a C1-6 alkyl group that may have 1 to 3 substituents selected from the Substituent Group , a C1-6 alkylcarbonyl group that may have 1 to 3 substituents selected from the Group Substituent , a C6-14-aryl carbonyl group which may have 1 to 3 substituents selected from the Substituent Group , a C1-6 alkyl sulfonyl group which may have 1 to 3 substituents selected from the Substituent Group , a C6-aryl group 14-sulfonyl which may have 1 to 3 substituents selected from the Substituent Group , a C3-8 carbocyclic group that may have 1 to 3 substituents selected from the Substituent Group , or a 5 to 10 membered heterocyclic group that may have 1 to 3 substituents selected from the Substituent Group , and

R3, R4, R5 and R6 are independently a hydrogen atom, a halogen atom, a hydroxy group, a C1-6 alkyl group which may have 1 to 3 substituents selected from the Substituent Group , a C1-6 alkoxy group which may have 1 to 3 substituents selected from the Substituent Group , a carbocyclic group of 3 to 10 members that may have 1 to 3 substituents selected from the Substituent Group

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, or a 5-10 membered heterocyclic group that may have 1 to 3 substituents selected from the Substituent Group 

[Substituent Group : a hydrogen atom, a halogen atom, a hydroxy group, a nitro group, a C1-6-thio alkyl group, a C6-14 aryl group, a C6-14-oxycarbonyl aryl group, a C6-14-aryl-carbonyl group, a cyano group, a C3-8 cycloalkoxy group, a C3-8 cycloalkyl group, a C3-8-thio cycloalkyl group, a sulfonylamino group (in which the sulfonylamino group may be substituted with 1 to 2 C1-6 alkyl groups), a C2-6 alkenyl group that may have 1 to 2 substituents selected from the Substituent Group , a C2-6 alkynyl group that may have 1 to 2 substituents selected from the Substituent Group , a carbamoyl group that may be substituted with 1 to 2 C1-6 alkyl groups, a C1-6 alkoxy group that may have 1 to 3 substituents selected from the Substituent Group , a C1-6 alkyl group that may have 1 to 3 substituents selected from the Substituent Group , and a 5-10 membered heterocyclic group that can 1 to 3 substituents selected from the Substituent Group ,

Substituent Group : a halogen atom, a cyano group, a hydroxy group and a C1-6 alkoxy group];

[4] The compound or pharmaceutically acceptable salt thereof, or solvate thereof according to any one of [1] to [3] above, wherein X is a methylene group which may have 1 to 2 substituents selected from the Substituent Group ;

[5] The compound or pharmaceutically acceptable salt thereof, or solvate thereof according to any one of [1] to [4] above, wherein Z is an oxygen atom and Y is a C1-3 alkylene group which can have 1 to 3 substituents selected from the Substituent Group ;

[6] The compound or pharmaceutically acceptable salt thereof, or solvate thereof according to any one of [1] to [4] above, wherein Z is an oxygen atom and Y is a C2-3 alkenylene group that can have 1 to 3 substituents selected from the Substituent Group ;

[7] The compound or pharmaceutically acceptable salt thereof, or solvate thereof according to any one of [1] to [4] above, wherein Z is a sulfur atom or a sulfone and Y is a C1- alkylene group 3 which may have 1 to 3 substituents selected from the Substituent Group ;

[8] The compound or pharmaceutically acceptable salt thereof, or solvate thereof according to any one of [1] to [4] above, wherein L is NRLCO- (wherein RL is a hydrogen atom or an alkyl group C1-6 which may have 1 to 3 substituents selected from the Substituent Group );

[9] The compound or pharmaceutically acceptable salt thereof, or solvate thereof according to any one of [1] to [8] above, wherein the substituents selected from the Substituent Group  is a hydrogen atom, a halogen atom, a C1-6 alkoxy group that may have 1 to 3 substituents selected from the Substituent Group , or a C1-6 alkyl group that may have 1 to 3 substituents selected from the Substituent Group .

[10] A compound or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the compound is selected from the following compounds:

1) N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-8a-yl) -4-fluorophenyl] -5cianopyridin-2-carboxamide,

2) N- [3 - ((8S *, 8aR *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-8a-yl) -4-fluorophenyl] -5fluoromethoxypyrazin-2-carboxamide,

3) N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-8a-yl) -4-fluorophenyl] -5difluoromethoxypyrazin-2-carboxamide,

4) N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-8a-yl) -4-trifluoromethoxyphenyl] -5cianopyridin-2-carboxamide,

5) N- [3 - ((8S *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-8a-yl) -4-trifluoromethoxyphenyl] -5chloropyridin-2-carboxamide,

6) N- [3 - ((4aR *, 6S *, 8aS *) - 2-amino-6-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4fluorophenyl] -5-chloropyridin-2-carboxamide,

7) N- [3 - ((4aR *, 6S *, 8aS *) - 2-amino-6-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4fluorophenyl] -5-cyanopyridin-2-carboxamide,

8) N- [3 - ((4aR *, 6S *, 8aS *) - 2-amino-6-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4fluorophenyl] -5-trifluoromethylpyridin-2-carboxamide,

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9) N- [3 - ((4aR *, 6S *, 8aS *) - 2-amino-6-methyl-4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen -8a-yl) -4-fluorophenyl] 5-difluoromethoxypyrazin-2-carboxamide,

10) N- [3 - ((4aR *, 6S *, 8aS *) - 2-amino-6-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-il) -4fluorophenyl] -5-fluoromethoxypyrazin-2-carboxamide,

11) N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-methoxymethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4fluorophenyl] -5-cyanopyridin-2-carboxamide,

12) N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-methoxymethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-il) -4fluorophenyl] -5-difluoromethylpyrazin-2-carboxamide,

13) N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-methoxymethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4fluorophenyl] -5-chloropyridin-2-carboxamide,

14) N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-methoxymethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-il) -4fluorophenyl] -5-fluoromethoxypyrazin-2-carboxamide,

15) N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-methoxymethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-il) -4fluorophenyl] -5-difluoromethoxypyrazin-2-carboxamide,

16) N- [3 - ((4aS, 5S, 8aS) -2-amino-5-fluoro-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen- 8a-yl-4-fluorophenyl] 5-cyanopyridin-2-carboxamide,

17) N- [3 - ((4aS, 5S, 8aS) -2-amino-5-fluoro-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen- 8a-yl) -4fluorophenyl] -5-difluoromethylpyrazin-2-carboxamide,

18) N- [3 - ((4aS, 5S, 8aS) -2-amino-5-fluoro-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen- 8a-yl) -4fluorophenyl] -5-chloropyridin-2-carboxamide,

19) N- [3 - ((4aS, 5S, 8aS) -2-amino-5-fluoro-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen- 8a-yl) -4fluorophenyl] -5-trifluoromethylpyridin-2-carboxamide,

20) N- [3 - ((4aS, 5S, 8aS) -2-amino-5-fluoro-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen- 8a-yl) -4fluorophenyl] -5-difluoromethoxypyridin-2-carboxamide,

21) N- [3 - ((4aS, 5S, 8aS) -2-amino-5-fluoro-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen- 8a-yl) -4fluorophenyl] -5-fluoromethoxypyrazin-2-carboxamide,

22) N- [3 - ((4aS, 5S, 8aS) -2-amino-5-fluoro-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen- 8a-yl) -4fluorophenyl] -5-difluoromethoxypyrazin-2-carboxamide,

23) N- [3 - ((4aR *, 5S *, 8aS *) - 2-amino-5-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4fluorophenyl] -5-chloropyridin-2-carboxamide,

24) N- [3 - ((4aR *, 5S * .8aS *) - 2-amino-5-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4fluorophenyl] -5-cyanopyridin-2-carboxamide,

25) N- [3 - ((4aR *, 5S *, 8aS *) - 2-amino-5-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-il) -4fluorophenyl] -5-difluoromethoxypyrazin-2-carboxamide,

26) N- [3 - ((4aR *, 5R *, 8aS *) - 2-amino-5-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4fluorophenyl] -5-chloropyridin-2-carboxamide,

27) N- [3 - ((4aR *, 5R *, 8aS *) - 2-amino-5-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4fluorophenyl] -5-cyanopyridin-2-carboxamide,

28) N- [3 - ((4aR *, 5R *, 8aS *) - 2-amino-5-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-il) -4fluorophenyl] -5-difluoromethoxypyrazin-2-carboxamide,

29) N- [3 - ((4aR *, 5R *, 8aS *) - 2-amino-5-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-il) -4fluorophenyl] -5-difluoromethylpyrazin-2-carboxamide,

30) N- [3 - ((4aS *, 5R *, 8aS *) - 2-amino-5-methoxy-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4fluorophenyl] -5-cyanopyridin-2-carboxamide,

31) N- [3 - ((2R *, 4aR *, 8aS *) - 2-amino-4-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4fluorophenyl] -5-cyanopyridin-2-carboxamide,

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32) N- [3 - ((2R *, 4aR *, 8aS *) - 2-amino-4-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-il) -4fluorophenyl] -5-difluoromethylpyrazin-2-carboxamide,

33) N- [3 - ((4aR, 6R, 8aS) -2-amino-6-hydroxymethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen- 8a-yl) -4fluorophenyl] -5-chloropyridin-2-carboxamide,

34) N- [3 - ((4aR, 6R, 8aS) -2-amino-6-hydroxymethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen- 8a-yl) -4fluorophenyl] -5-cyanopyridin-2-carboxamide,

35) N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-trifluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4fluorophenyl] -5-cyanopyridin-2-carboxamide,

36) N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-trifluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-il) -4fluorophenyl] -5-difluoromethoxypyrazin-2-carboxamide,

37) N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-trifluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4fluorophenyl] -5-fluoropyridin-2-carboxamide,

38) N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-trifluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4fluorophenyl] -pyridin-2-carboxamide,

39) N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-trifluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-il) -4fluorophenyl] -5-fluoromethoxypyrazin-2-carboxamide,

40) N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-trifluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-il) -4fluorophenyl] -pyrimidin-4-carboxamide,

41) N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-trifluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4fluorophenyl] -3,5-difluoropyridin-2-carboxamide,

42) N- (3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-trifluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4fluorophenyl] -5-difluoromethoxypyridin-2-carboxamide,

43) N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-trifluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-il) -4fluorophenyl] -5-difluoromethylpyrazin-2-carboxamide,

44) N- [3 - ((4aR, 6R, 8aS) -2-amino-6-fluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen- 8a-yl) -4fluorophenyl] -5-cyanopyridin-2-carboxamide,

45) N- [3 - ((4aR, 6R, 8aS) -2-amino-6-fluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen- 8a-yl) -4fluorophenyl] -5-chloropyridin-2-carboxamide,

46) N- [3 - ((4aR, 6R, 8aS) -2-amino-6-fluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen- 8a-yl) -4fluorophenyl] -5-trifluoromethylpyridin-2-carboxamide,

47) N- [3 - ((4aR, 6R, 8aS) -2-amino-6-fluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen- 8a-yl) -4fluorophenyl] -5-fluoromethoxypyrazin-2-carboxamide,

48) N- [3 - ((4aR, 6R, 8aS) -2-amino-6-fluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen- 8a-yl) -4fluorophenyl] -5-difluoromethylpyrazin-2-carboxamide,

49) N- [3 - ((4aR *, 8aS *) 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-8a-yl) - 4-fluorophenyl] -5chloropyridin-2-carboxamide,

50) N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-8a-yl) -4-fluorophenyl] -5bromopyridin-2-carboxamide,

51) N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-8a-yl) -4-fluorophenyl] -3,5difluoropyridin-2-carboxamide,

52) N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-8a-yl) -4-fluorophenyl] -3,5-dichloropyridin-2-carboxamide,

53) N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-8a-yl) -4-fluorophenyl] -5fluoropyridin-2-carboxamide,

54) N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-8a-yl) -4-fluorophenyl] -3,5-dibromopyridin-2-carboxamide,

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55) N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-8a-yl) -4-fluorophenyl] -5trifluoromethylpyridin-2-carboxamide,

56) N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-8a-yl) -4-fluorophenyl] -5difluoromethylpyridin-2-carboxamide,

57) N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-8a-yl) -4-fluorophenyl] -5difluoromethylpyrazin-2-carboxamide,

58) N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-8a-yl) -4 -fluorophenyl] -5difluoromethoxypyridin-2-carboxamide,

59) (±) - (4aR *, 6R *, 8aS *) - 8a- [2-fluoro-5- (2-fluoropyridin-3-yl) phenyl] -6-trifluoromethyl-4,4a, 5,6, 8,8a-hexahydro-7-oxa3-thia-1-azanaphthalen-2-ylamine,

60) (4aR, 6R, 8aS) -8a- [2-fluoro-5- (2-fluoropyridin-3-yl) phenyl] -6-fluoromethyl-4,4a, 5,6,8,8a-hexahydro-7 -oxa-3-tia-1azanaftalen-2-ylamine,

61) (±) - (4aR *, 8aS *) - 8a- [2-fluoro-5- (2-fluoropyridin-3-yl) phenyl] -4,4a, 5,6,8,8a-hexahydro-7 -oxa-3-thia-1-azanaphthalen2-ylamine,

62) (±) - (4aR *, 8aS *) - 8a- (2-fluoro-5-pyrimidin-5-ylphenyl) -4,4a, 5,6,8,8a-hexahydro-7-oxa-3- thia-1-azanaphthalen-2-amine,

63) (±) - (4aR *, 8aS *) - 8a- [5- (5-chloropyridin-3-yl) -2-fluorophenyl] -4,4a, 5,6,8,8a-hexahydro-7- oxa-3-thia-1-azanaphthalen2-ylamine,

64) N- [5 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-8a-yl) thiophene-3-yl] -5cianopyridin-2-carboxamide,

65) (±) - (4aR *, 8aR *) - 8a- [4- (2-fluoropyridin-3-yl) -thiophene-2-yl] -4,4a, 5,6,8,8a-hexahydro- 7-oxa-3-thia-1-azanaphthalen-2-amine,

66) (4aR, 6R, 8aS) -8a- [2-fluoro-5- (2-fluoropyridin-3-yl) phenyl] -6-benzyloxymethyl-4,4a, 5,6,8,8a-hexahydro-7 -oxa-3-thia1-azanaphthalen-2-ylamine,

67) (±) -N- [7 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen- 8a-yl) -2,2difluorobenzo [1,3] dioxol-5-yl] -5-cyanopyridin-2-carboxamide,

68) N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-8a-yl) -4-fluorophenyl] -5- (2-methoxyethoxy) -pyrazin-2-carboxamide,

69) N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-8a-yl) -4-fluorophenyl] -2methylthiazol-4-carboxamide,

70) N- [3 - ((4aR *, 5R *, 8aS *) - 2-amino-5-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4fluorophenyl] -2,5-dimethylfuran-3-carboxamide,

71) N- [3 - ((4aR *, 5R *, 8aS *) - 2-amino-5-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4fluorophenyl] -4-methyl- [1,2,3] thiadiazol-5-carboxamide,

72) N- [3 - ((4aR *, 5R *, 8aS *) - 2-amino-5-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4fluorophenyl] -3-piperidin-1-ylpropionamide, and

73) N- [3 - ((4aR *, 5R *, 8aS *) - 2-amino-5-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4fluorophenyl] -2-methylxazol-4-carboxamide,

or a pharmaceutically acceptable salt thereof, or a solvate thereof;

[11] A pharmaceutical composition comprising as active ingredient the compound or pharmaceutically acceptable salt thereof, or solvate thereof according to any one of [1] to [10] above;

[12] The pharmaceutical composition according to [11] above, to inhibit the production of -amyloid protein;

[13] The pharmaceutical composition according to [11] above, to inhibit enzyme 1 cleavage of the beta-site -amyloid precursor protein (BACE1);

[14] The pharmaceutical composition according to any one of [11] to [13] above, to treat a neurodegenerative disease; Y

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[15] The pharmaceutical composition according to [14] above, in which the neurodegenerative disease is Alzheimer's dementia or Down syndrome. Advantages of the invention

The present invention can provide a compound represented by the general formula: [Formula 6]

image6

wherein Ring A is a C6-14 aryl group or similar, L is -NRLCO- or similar (where RL is a hydrogen atom or similar), Ring B is a C6-14 aryl group or similar, X is a C1-3 alkylene group or the like, Y is a C1-3 alkylene group or the like, Z is an oxygen atom or the like, R1 and R2 are each independently a hydrogen atom or the like, and R3, R4, R5 and R6 are independently a hydrogen atom, a halogen atom or the like, or a pharmaceutically acceptable salt thereof or a solvate thereof. The compound of the present invention has an inhibitory effect on the production of A or an inhibitory effect on BACE1, and is useful as a therapeutic agent for a neurodegenerative disease caused by A and typified by Alzheimer's dementia.

Mode for carrying out the invention

The meaning of symbols, terms and the like used herein will be explained below, and the present invention will be described in detail.

In the present specification, a structural formula of a compound may conveniently represent a certain isomer. However, the present invention includes all isomers and mixtures of isomers, such as geometric isomers that can be generated from the structure of a compound, asymmetric carbon-based optical isomers, stereoisomers and tautomers. The present invention is not limited to the description of a chemical formula for convenience, and may include any one of the isomers or mixtures thereof. Accordingly, the compound of the present invention may have an asymmetric carbon atom in the molecule and exist as an optically active compound or racemate, and the present invention includes each of the optically active compounds and racemates without limitations. Although crystalline polymorphs of the compound may be present, similarly the compound is not limited thereto, and may be present as an individual crystalline form or as a mixture of individual crystalline forms. The compound can be an anhydride or a hydrate. Any of these forms is included in the claims of the present specification.

The "halogen atom" herein refers to a fluorine atom, a chlorine atom, a bromine atom, an iodine atom or the like, and is preferably a fluorine atom or a chlorine atom.

The "C1-6 alkyl group" refers to an alkyl group having 1 to 6 carbon atoms. Preferable examples of the group include linear or branched alkyl groups, such as a methyl group, an ethyl group, an npropyl group, an isopropyl group, an n-butyl group, an isobutyl group, a t-butyl group, an n- group pentyl, an isopentyl group, a neopentyl group, an n-hexyl group, a 1-methylpropyl group, a 1,2-dimethylpropyl group, a 1-ethylpropyl group, a 1-methyl-2-ethylpropyl group, a 1-ethyl- group 2-methylpropyl, a 1,1,2-trimethylpropyl group, a 1-methylbutyl group, a 2-methylbutyl group, a 1,1-dimethylbutyl group, a 2,2-dimethylbutyl group, a 2-ethylbutyl group, a group 1, 3-dimethylbutyl, a 2-methylpentyl group and a 3-methylpentyl group. The group is more preferably a methyl group, an ethyl group or an n-propyl group.

The "C2-6 alkenyl group" refers to an alkenyl group having 2 to 6 carbon atoms. Preferable examples of the group include linear or branched alkenyl groups, such as a vinyl group, an allyl group, a 1-propenyl group, an isopropenyl group, a 1-buten-1-yl group, a 1-buten-2- group ilo, a 1-buten-3-yl group, a 2-buten-1-yl group and a 2-buten-2-yl group.

The "C2-6 alkynyl group" refers to an alkynyl group having 2 to 6 carbon atoms. Preferable examples of the group include linear or branched alkynyl groups, such as an ethynyl group, a 1-propynyl group, a 2-propynyl group, a butynyl group, a pentinyl group and a hexinyl group.

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The group "C1-6 alkoxy" refers to an alkyl group having 1 to 6 carbon atoms in which a hydrogen atom is replaced by an oxygen atom. Examples of the group include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, a tbutoxy group, an n-pentoxy group, a isopentoxy group, a sec-pentoxy group, a t-pentoxy group, an n-hexoxy group, an isohexoxy group, a 1,2-dimethylpropoxy group, a 2-ethylpropoxy group, a 1-methyl-2-ethylpropoxy group, a 1-ethyl-2-methylpropoxy group, a 1,1,2-trimethylpropoxy group, a 1,1-dimethylbutoxy group, a 2,2-dimethylbutoxy group, a 2-ethylbutoxy group, a 1,3-dimethylbutoxy group, a 2-methylpentoxy group , a 3-methylpentoxy group and a hexyloxy group.

The "C1-6-thio alkyl group" refers to an alkyl group having 1 to 6 carbon atoms in which a hydrogen atom is replaced by a sulfur atom. Examples of the group include a methylthio group, an ethylthio group, an n-propylthio group, an isopropylthio group, a butylthio group, an isobutylthio group, a t-butylthio group, an n-pentylthio group, an isopentylthio group, a neopentylthio group , a hexylthio group and a 1-methylpropylthio group.

The "C1-6 alkyl sulfonyl group" refers to an alkyl group having 1 to 6 carbon atoms in which a hydrogen atom is replaced by a sulfonyl group. Examples of the group include a methylsulfonyl group, an ethylsulfonyl group, an n-propylsulfonyl group, an isopropylsulfonyl group, an n-butylsulfonyl group, an isobutyl sulfonyl group, a t-butylsulfonyl group, an n-pentylsulfonyl group, an isopentylsulfonyl group, a neopentylsulfonyl group, an n-hexylsulfonyl group and a 1-methylpropylsulfonyl group.

The "C1-6 alkylcarbonyl group" refers to an alkyl group having 1 to 6 carbon atoms in which a hydrogen atom is replaced by a carbonyl group. Preferable examples of the group include an acetyl group, a propionyl group and a butyryl group.

The "C6-14 aryl group" refers to an aromatic hydrocarbon ring group having 6 to 14 carbon atoms. Examples of the group include a phenyl group, a naphthyl group and an antryl group. Particularly preferable is a phenyl group.

The "C7-12 aralkyl group" refers to a group having 7 to 12 carbon atoms in which an aromatic ring such as a phenyl group or a naphthyl group is substituted with a C1-6 alkyl group. Examples of the group include a benzyl group, a phenethyl group, a phenylpropyl group and a naphthylmethyl group. A benzyl group is particularly preferable.

The "C6-14-oxycarbonyl aryl group" refers to a group in which carbonyl is linked to an aromatic ring having 6 to 14 carbon atoms. Preferable examples of the group include a phenyloxycarbonyl group, a naphthyloxycarbonyl group and an anthyloxycarbonyl group. A phenyloxycarbonyl group is more preferable.

The "C6-14-aryl carbonyl group" refers to a group in which a carbonyl group is linked to an aromatic ring having 6 to 14 carbon atoms. Preferable examples of the group include a benzoyl group and a naphthoyl group. A benzoyl group is more preferable.

The "C6-14-aryl sulfonyl group" refers to a group in which a sulfonyl group is linked to an aromatic ring having 6 to 14 carbon atoms. Preferable examples of the group include a benzylsulfonyl group and a naphthylsulfonyl group. A benzyl sulfonyl group is more preferable.

The "C3-8 cycloalkyl group" refers to a cyclic alkyl group having 3 to 8 carbon atoms. Preferable examples of the group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group and a cyclooctyl group.

The "C3-8 cycloalkyloxy group" refers to a cyclic alkyl group having 3 to 8 carbon atoms in which a hydrogen atom is replaced by an oxygen atom. Examples of the group include a cyclopropoxy group, a cyclobutoxy group, a cyclopentoxy group, a cyclohexoxy group, a cycloheptyloxy group and a cyclooctyloxy group.

The "C3-8-thio cycloalkyl group" refers to a cyclic alkyl group having 3 to 8 carbon atoms in which a hydrogen atom is replaced by a sulfur atom. Examples of the group include a cyclopropylthio group, a cyclobutylthio group, a cyclopentylthio group, a cyclohexylthio group, a cycloheptylthio group and a cyclooctylthio group.

The "5-10 membered heterocyclic group" refers to a cyclic group containing heteroatom, which has 5 to 10 members in total. Preferable examples of the group include a piperidinyl group, a pyrrolidinyl group, an azepinyl group, an azocanyl group, a piperazinyl group, a 1,4-diazepanyl group, a morpholinyl group, a thiomorpholinyl group, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a pyridinyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a triazolyl group, a triazinyl group, a tetrazolyl group, an isoxazolyl group, an oxazolyl group, an oxadiazolyl group, an isothiazolyl group, a group thiazolyl, a thiadiazolyl group, a furyl group, a thienyl group, a quinolinyl group, an isoquinolinyl group, a benzofuryl group, a benzopyranyl group, a benzimidazolyl group, a benzotriazolyl group, a benzothiazolyl group, an indolinyl group, an isoindolinyl group, a chromanyl group, an isochromanyl group, a 1,3-dioxaindanyl group, a 1,4-dioxatetralinyl group, a tetrahydrofuranyl group and a tetrahydropyranyl group.

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The "5-6 membered heteroaryl group" refers to the "5-10 membered heterocyclic group" which is a heteroatom-containing aromatic cyclic group, which has 5 to 6 members in total. Examples of the group include a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a pyridinyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a triazolyl group, a triazinyl group, a tetrazolyl group, an isoxazolyl group, a oxazolyl group, an oxadiazolyl group, an isothiazolyl group, a thiazolyl group, a thiadiazolyl group, a furyl group and a thienyl group.

The "9 to 10-membered benzo-condensed heterocyclic group" refers to the "5 to 10-membered heterocyclic group" which is a heteroatom-containing cyclic group, which has 9 to 10 members in total condensed with a benzene ring. Preferable examples of the group include an indolinyl group, an isoindolinyl group, a chromanyl group, an isochromanyl group, a 1,3-dioxaindanyl group and a 1,4-dioxatetralinyl group.

The "carbocyclic group of 3 to 10 members" refers to a carbocyclic group that has 3 to 10 members in total. Preferable examples of the group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, an [3,4] octanyl group, a decanyl group, an indanyl group, a 1-acenaphtenyl group , a cyclopentacylooctenyl group, a benzocyclooctenyl group, an indenyl group, a tetrahydronaphthyl group, a 6,7,8,9-tetrahydro-5H-benzocycloheptenyl group and a 1,4-dihydronaphthalenyl group.

The "C1-6 alkylene group" refers to a divalent group derived by excluding any hydrogen atom from the "C1-6 alkyl group" as defined above. Examples of the group include a methylene group, a 1,2-ethylene group, a 1,1-ethylene group, a 1,3-propylene group, a tetramethylene group, a pentamethylene group and a hexamethylene group.

The "C2-6 alkenylene group" refers to a divalent group derived by excluding any hydrogen atom from the "C2-6 alkenyl group" as defined above. Examples of the group include a 1,2-vinyl group (ethenylene group), a propethylene group, a butenylene group, a pentenylene group and a hexenylene group.

The "C2-6 alkynylene group" refers to a divalent group derived by excluding any hydrogen atom from the "C2-6 alkynyl group" as defined above. Examples of the group include an ethinylene group, a propynylene group, a butynylene group, a pentinylene group and a hexinylene group.

Examples of the "C1-3 alkylene group" include a methylene group, an ethylene group and a propylene group.

Examples of the "C2-3 alkynylene group" include an ethynylene group and a propynylene group.

Examples of the sulfonylamino group that may be substituted with a C1-6 alkyl group in the "sulfonylamino group (in which the sulfonylamino group may be substituted with a C1-6 alkyl group)" include a methylsulfonylmethylamino group, an ethylsulfonylmethylamino group and an ethylsulfonylethylamino group.

"Substituent Group " refers to a hydrogen atom, a halogen atom, a hydroxy group, a nitro group, a C1-6-thio alkyl group, a C6-14 aryl group, a C6-14- aryl group oxycarbonyl, a C6-14-aryl group, a cyano group, a C3-8 cycloalkoxy group, a C3-8 cycloalkyl group, a C3-8-thio cycloalkyl group, a sulfonylamino group (in which the sulfonylamino group it may be substituted with 1 to 2 C1-6 alkyl groups), an alkenyl group which may have 1 to 2 substituents selected from the Substituent Group , a C2-6 alkynyl group which may have 1 to 2 substituents selected from the Substituent Group  , a carbamoyl group that may be substituted with 1 to 2 C1-6 alkyl groups, a C1-6 alkoxy group that may have 1 to 3 substituents selected from the Substituent Group , a C1-6 alkyl group that may have 1 3 substituents selected from the Substituent Group , and a 5-10 membered heterocyclic group that may have 1 to 3 substituents selected from the Substituent Group .

"Substituent Group " refers to a halogen atom, a cyano group, a hydroxy group and a C1-6 alkoxy group (in which the alkoxy group may be substituted with a phenyl group which may be substituted with 1 to 3 substituents selected from a hydrogen atom, a halogen atom, a hydroxy group and a nitro group).

The condensed aminodihydrotiazine derivative of the formula (I) according to the present invention may be a pharmaceutically acceptable salt. Specific examples of the pharmaceutically acceptable salt include salts of inorganic acids (such as sulfates, nitrates, perchlorates, phosphates, carbonates, bicarbonates, hydrofluorides, hydrochlorides, hydrobromides and hydroiodides), organic carboxylates (such as acetates, oxalates, maleates, tartrates, smokers and citrates), organic sulfonates (such as methanesulfonates, trifluoromethanesulfonates, ethanesulfonates, benzenesulfonates, toluenesulfonates and canfosulfonates), amino acid salts (such as aspartates and glutamates), quaternary amine salts, alkali metal salts (such as sodium salts and potassium salts) and alkaline earth metal salts (such as magnesium salts and calcium salts).

The condensed aminodihydrotiazine derivative of the formula (I) or pharmaceutically acceptable salt thereof according to the present invention may be a solvate thereof. Examples of solvate include a hydrate.

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The compound (I) is not limited to a specific isomer, and includes all possible isomers (such as a keto-enol isomer, an imine-enamine isomer, a diastereoisomer, an optical isomer and a rotamer) and racemates. For example, the compound (I) in which R1 is hydrogen includes the following tautomers.

[Formula 7]

image7

5

The condensed aminodihydrotiazine derivative of the formula (I) according to the present invention is preferably a compound of the formula (I), wherein X is a methylene group which may have 1 to 2 substituents selected from the Substituent Group .

The condensed aminodihydrotiazine derivative of the formula (I) according to the present invention is also

Preferably a compound of the formula (I), wherein Z is an oxygen atom and Y is a C13 alkylene group which may have 1 to 3 substituents selected from the Substituent Group ; or Z is a sulfur atom or a sulfone and Y is a C1-3 alkylene group which may have a substituent selected from the Substituent Group .

The condensed aminodihydrotiazine derivative of the formula (I) according to the present invention is further preferably a compound of the formula (I), wherein L is -NRLCO- (wherein RL is a hydrogen atom or an alkyl group of C1-6 which may have 1 to 3 substituents selected from the Substituent Group ).

Preferable compounds in the present invention include the following compounds:

1) N- [3 - ((4aR *, 8aS *) - 2-amino-4-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-8a- il) -4-fluorophenyl] -5cianopyridin-2-carboxamide,

2) N- [3 - ((8S *, 8aR *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-8a-yl) -4-fluorophenyl] -520 fluoromethoxypyrazin-2-carboxamide,

3) N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-8a-yl) -4-fluorophenyl] -5difluoromethoxypyrazin-2-carboxamide,

4) N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-8a-yl) -4-trifluoromethoxyphenyl] -5cianopyridin-2-carboxamide,

25 5) N- [3 - ((8S *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-8a-il ) -4-trifluoromethoxyphenyl] -5chloropyridin-2-carboxamide,

6) N- [3 - ((4aR *, 6S *, 8aS *) - 2-amino-6-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-il) -4-fluorophenyl] -5chloropyridin-2-carboxamide,

7) N- [3 - ((4aR *, 6S *, 8aS *) - 2-amino-6-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-il) -4-fluorophenyl] -530 cyanopyridine-2-carboxamide,

8) N- [3 - ((4aR *, 6S *, 8aS *) - 2-amino-6-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4-fluorophenyl] -5trifluoromethylpyridin-2-carboxamide,

9) N- [3 - ((4aR *, 6S *, 8aS *) - 2-amino-6-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-il) -4-fluorophenyl] -5difluoromethoxypyrazin-2-carboxamide,

10 10) N- [3 - ((4aR *, 6S *, 8aS *) - 2-amino-6-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia- 1-azanaphthalen-8a-yl) -4-fluorophenyl] 5-fluoromethoxypyrazin-2-carboxamide,

11) N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-methoxymethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4fluorophenyl] -5-cyanopyridin-2-carboxamide,

12) N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-methoxymethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-il-440 fluorophenyl] -5-difluoromethylpyrazin-2-carboxamide,

13) N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-methoxymethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4fluorophenyl] -5-chloropyridin-2-carboxamide,

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14) N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-methoxymethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-il) -4fluorophenyl] -5-fluoromethoxypyrazin-2-carboxamide,

15) N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-methoxymethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-il) -4fluorophenyl] -5-difluoromethoxypyrazin-2-carboxamide,

16) N- [3 - ((4aS, 5S, 8aS) -2-amino-5-fluoro-4,4a, 5,5,6,8,8a-hexahydro-7-oxa-3-thia-1- azanaftalen-8a-yl) -4-fluorophenyl] 5-cyanopyridin-2-carboxamide,

17) N- [3 - ((4aS, 5S, 8aS) -2-amino-5-fluoro-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen- 8a-yl) -4-fluorophenyl] -5difluoromethylpyrazin-2-carboxamide,

18) N- [3 - ((4aS, 5S, 8aS) -2-amino-5-fluoro-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen- 8a-yl) -4-fluorophenyl] -5-chloropyridin-2-carboxamide,

19) N- [3 - ((4aS, 5S, 8aS) -2-amino-5-fluoro-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen- 8a-yl) -4-fluorophenyl] -5trifluoromethylpyridin-2-carboxamide,

20) N- [3 - ((4aS, 5S, 8aS) -2-amino-5-fluoro-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen- 8a-yl) -4-fluorophenyl] -5difluoromethoxypyridin-2-carboxamide,

21) N- [3 - ((4aS, 5S, 8aS) -2-amino-5-fluoro-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen- 8a-yl) -4-fluorophenyl] -5fluoromethoxypyrazin-2-carboxamide,

22) N- [3 - ((4aS, 5S, 8aS) -2-amino-5-fluoro-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen- 8a-yl) -4-fluorophenyl] -5difluoromethoxypyrazin-2-carboxamide,

23) N- [3 - ((4aR * -5S * -8aS *) - 2-amino-5-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4-fluorophenyl] 5-chloropyridin-2-carboxamide,

24) N- [3 - ((4aR *, 5S *, 8aS *) - 2-amino-5-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4-fluorophenyl] 5-cyanopyridin-2-carboxamide,

25) N- [3 - ((4aR *, 5S *, 8aS *) - 2-amino-5-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4-fluorophenyl] 5-difluoromethoxypyrazin-2-carboxamide,

26) N- [3 - ((4aR *, 5R *, 8aS *) - 2-amino-5-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4-fluorophenyl] 5-chloropyridin-2-carboxamide,

27) N- [3 - ((4aR *, 5R *, 8aS *) - 2-amino-5-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4-fluorophenyl] 5-cyanopyridin-2-carboxamide,

28) N- [3 - ((4aR *, 5R *, 8aS *) - 2-amino-5-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4-fluorophenyl] 5-difluoromethoxypyrazin-2-carboxamide,

29) N- [3 - ((4aR *, 5R *, 8aS *) - 2-amino-5-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4-fluorophenyl] 5-difluoromethylpyrazin-2-carboxamide,

30) N- [3 - ((4aS *, 5R *, 8aS *) - 2-amino-5-methoxy-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4fluorophenyl] -5-cyanopyridin-2-carboxamide,

31) N- [3 - ((2R *, 4aR *, 8aS *) - 2-amino-4-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4-fluorophenyl] 5-cyanopyridin-2-carboxamide,

32) N- [3 - ((2R *, 4aR *, 8aS *) - 2-amino-4-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4-fluorophenyl] 5-difluoromethylpyrazin-2-carboxamide,

33) N- [3 - ((4aR, 6R, 8aS) -2-amino-6-hydroxymethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen- 8a-yl) -4fluorophenyl] -5-chloropyridin-2-carboxamide,

34) N- [3 - ((4aR, 6R, 8aS) -2-amino-6-hydroxymethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen- 8a-yl) -4fluorophenyl] -5-cyanopyridin-2-carboxamide,

35) N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-trifluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4fluorophenyl] -5-cyanopyridin-2-carboxamide,

36) N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-trifluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-il) -4fluorophenyl] -5-difluoromethoxypyrazin-2-carboxamide,

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37) N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-trifluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4fluorophenyl] -5-fluoropyridin-2-carboxamide,

38) N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-trifluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4fluorophenyl] -pyridin-2-carboxamide,

39) N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-trifluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-il) -4fluorophenyl] -5-fluoromethoxypyrazin-2-carboxamide,

40) N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-trifluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-il) -4fluorophenyl] -pyrimidin-4-carboxamide,

41) N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-trifluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4fluorophenyl] -3,5-difluoropyridin-2-carboxamide,

42) N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-trifluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4fluorophenyl] -5-difluoromethoxypyridin-2-carboxamide,

43) N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-trifluoromethyl-4,4a, 5,6,8,8a-hexahdro-7-oxa-3-tia-1 -azanaftalen-8a-il) -4fluorophenyl] -5-difluoromethylpyrazin-2-carboxamide,

44) N- [3 - ((4aR, 6R, 8aS) -2-amino-6-fluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen- 8a-yl) -4fluorophenyl] -5-cyanopyridin-2-carboxamide,

45) N- [3 - ((4aR, 6R, 8aS) -2-amino-6-fluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen- 8a-yl) -4fluorophenyl] -5-chloropyridin-2-carboxamide,

46) N- [3 - ((4aR, 6R, 8aS) -2-amino-6-fluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen- 8a-yl) -4fluorophenyl] -5-trifluoromethylpyridin-2-carboxamide,

47) N- [3 - ((4aR, 6R, 8aS) -2-amino-6-fluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen- 8a-yl) -4fluorophenyl] -5-fluoromethoxypyrazin-2-carboxamide,

48) N- [3 - ((4aR, 6R, 8aS) -2-amino-6-fluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen- 8a-yl) -4fluorophenyl] -5-difluoromethylpyrazin-2-carboxamide,

49) N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-8a-yl) -4 -fluorophenyl] -5-chloropyridin2-carboxamide,

50) N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-8a-yl) -4-fluorophenyl] -5bromopyridin-2-carboxamide,

51) N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-8a-yl) -4-fluorophenyl] -3,5difluoropyridin-2-carboxamide,

52) N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-8a-yl) -4-fluorophenyl] -3,5-dichloropyridin-2-carboxamide,

53) N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-8a-yl) -4-fluorophenyl] -5fluoropyridin-2-carboxamide,

54) N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-8a-yl) -4-fluorophenyl] -3,5-dibromopyridin-2-carboxamide,

55) N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-8a-yl) -4-fluorophenyl] -5trifluoromethylpyridin-2-carboxamide,

56) N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-8a-yl) -4-fluorophenyl] -5difluoromethylpyridin-2-carboxamide,

57) N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-8a-yl) -4-fluorophenyl] -5difluoromethylpyrazin-2-carboxamide,

58) N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-8a-yl) -4-fluorophenyl] -5difluoromethoxypyridin-2-carboxamide,

59) (±) - (4aR *, 6R *, 8aS *) - 8a- [2-fluoro-5- (2-fluoropyridin-3-yl) phenyl] -6-trifluoromethyl-4,4a, 5,6, 8,8a-hexahydro-7-oxa-3thia-1-azanaphthalen-2-ylamine,

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60) (4aR, 6R, 8aS) -8a- [2-fluoro-5- (2-fluoropyridin-3-yl) phenyl] -6-fluoromethyl-4,4a, 5,6,8,8a-hexahydro-7 -oxa-3-tia-1azanaftalen-2-ylamine,

61) (±) - (4aR *, 8aS *) - 8a- [2-fluoro-5- (2-fluoropyridin-3-yl) phenyl] -4,4a, 5,6,8,8a-hexahydro-7 -oxa-3-thia-1-azanaphthalen-2-amine,

62) (±) - (4aR *, 8aS *) - 8a- (2-fluoro-5-pyrimidin-5-ylphenyl) -4,4a, 5,6,8,8a-hexahydro-7-oxa-3- thia-1-azanaphthalen-2-ylamine,

63) (±) - (4aR *, 8aS *) - 8a- [5- (5-chloropyridin-3-yl) -2-fluorophenyl] -4,4a, 5,6,8,8a-hexahydro-7- oxa-3-thia-1-azanaphthalen-2-amine,

64) N- [5 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-8a-yl) thiophen-3-yl] -5-cyanopyridin2-carboxamide,

65) (±) - (4aR *, 8aR *) - 8a- [4- (2-fluoropyridin-3-yl) -thiophene-2-yl] -4,4a, 5,6,8,8a-hexahydro- 7-oxa-3-thia-1-azanaphthalen-2-amine,

66) (4aR, 6R, 8aS) -8a- [2-fluoro-5- (2-fluoropyridin-3-yl) phenyl] -6-benzyloxymethyl-4,4a, 5,6,8,8a-hexahydro-7 -oxa-3-tia-1azanaftalen-2-ylamine,

67) (±) -N- [7 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen- 8a-yl) -2,2difluorobenzo [1,3] dioxol-5-yl] -5-cyanopyridin-2-carboxamide,

68) N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-8a-yl) -4-fluorophenyl] -5- (2-methoxyethoxy) -pyrazin-2-carboxamide,

69) N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-8a-yl) -4-fluorophenyl] -2-methylthiazol4-carboxamide,

70) N- [3 - ((4aR *, 5R *, 8aS *) - 2-amino-5-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4-fluorophenyl] 2,5-dimethylfuran-3-carboxamide,

71) N- [3 - ((4aR *, 5R *, 8aS *) - 2-amino-5-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4-fluorophenyl] 4-methyl- [1,2,3] thiadiazol-5-carboxamide,

72) N- [3 - ((4aR *, 5R *, 8aS *) - 2-amino-5-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4-fluorophenyl] 3-piperidin-1-ylpropionamide, and

73) N- [3 - ((4aR *, 5R *, 8aS *) 2-amino-5-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1- azanaftalen-8a-yl) -4-fluorophenyl] 2-methylxazol-4-carboxamide.

Next, methods for preparing the compound of formula (I) [hereinafter referred to as compound (I) will be described below; a compound represented by another formula is described similarly] or its pharmaceutically acceptable salt according to the present invention.

The "leaving group" in the compound of the raw material used in the preparation of the compound of the formula (I) according to the present invention can be any leaving group used for a nucleophilic substitution reaction. Preferable examples of the leaving group include a halogen atom, a C1-6 alkyl sulfonyloxy group that may be substituted with the above Substituent Group y, and an arylsulfonyloxy group that may be substituted with the previous Substituent Group . Specific examples of the leaving group include a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group and a ptoluenesulfonyloxy group.

1. General Preparation Method 1:

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In the formula, R7 represents a C1-6 alkyl group, such as a methyl group or an ethyl group, a C7-12 aralkyl group, such as a benzyl group, or the like, LV is a leaving group and represents an atom halogen (such as a chlorine atom, a bromine atom or an iodine atom), for example, or a sulfonyloxy group such as a group

5 methanesulfonyloxy, a p-toluenesulfonyloxy group or a trifluoromethanesulfonyloxy group, for example, and Ring A, R1, R2, R3, R4, R5, R6, Y and Z are as defined above.

The General Preparation Method 1 is a method for preparing a compound (1-7) which is a synthetic intermediate of the compound (I) according to the present invention from a compound (1-1) as a raw material through multiple stages from Stage 1-1 to Stage 1-6.

The compound (1-1) can be a commercially available product used as such, it can also be prepared from a commercially available product by a method known to a person skilled in the art, and can be further prepared by a described method. in the Preparation Examples, within the Examples.

1-1. Stage 1-1:

This step is a step to obtain a compound (1-2) by trifluoromethanesulfonylation of the compound (11).

The reaction at this stage can be carried out under the same conditions as those commonly used in the trifluoromethanesulfonylation reaction of a carbonyl compound (such as the conditions described in J. Org. Chem., 57, 6972-6975 (1992), Tetrahedron Letters., 40, 8133-8136 (1999) and Tetrahedron., 61, 4129-4140

(2)

ligadores escindibles tales como -S-S-, -O-Si-O-, monosacáridos (tales como un grupo glucosa y un grupo galactosa) y disacáridos (tales como lactosa), y ligadores oligopeptídicos escindibles enzimáticamente,

(3)

grupos de etiqueta de pesca tales como biotina y 3-(4,4-difluoro-5,7-dimetil-4H-3a,4a-diaza-4-bora-sindacen-3-il)propionilo,

(4)

marcadores detectables tales como grupos marcadores radioactivos tales como 125I, 32P, 3H y 14C; grupos marcadores fluorescentes tales como fluoresceína, rodamina, dansilo, umbeliferona, 7-nitrofurazanilo y 3(4,4-difluoro-5,7-dimetil-4H-3a,4a-diaza-4-bora-s-indacen-3-il)propionilo; grupos quimioluminiscentes tales como luciferina y luminol; e iones de metales pesados tales como iones de metales lantánidos y iones de radio, y

(5)

grupos unidos a soportes de fase sólida tales como perlas de vidrio, lechos de vidrio, placas de microtitulación, perlas de agarosa, lechos de agarosa, perlas de poliestireno, lechos de poliestireno, perlas de nailon y lechos de nailon.

Cuando una sonda se prepara introduciendo un grupo marcador o similar seleccionado del grupo que consiste en (1) a (5) anterior en el compuesto de la presente invención según un método descrito en los documentos anteriores o similar, la sonda se puede usar como una sonda química para la identificación de proteínas marcadas útiles para investigar, por ejemplo, nuevas dianas farmacéuticas.
La presente invención se describirá más específicamente a continuación con referencia a los Ejemplos, Ejemplos de Preparación, y Ejemplo de Ensayo. Sin embargo, la presente invención no está limitada a ellos. Las abreviaturas usadas en los Ejemplos son abreviaturas convencionales conocidas por una persona experta en la técnica. A continuación se muestran algunas abreviaturas.
THF: Tetrahidrofurano
DMF: N,N-dimetilformamida
TFA: Ácido trifluoroacético
EDC·HCl: Hidrocloruro de 1-etil-3-(3-dimetilaminopropil)carbodiimida
pTLC: Cromatografía de capa fina preparativa
LC-MS: Cromatografía de líquidos-espectrometría de masas
PyBOP: Hexafluorofosfato de benzotriazol-1-iloxitris(pirrolidino)fosfonio
Pd2DBA3: Tris(dibencilidenacetona)paladio
Pd(t-Bu3P)2: Bis(tri-t-butilfosfnina)paladio Los desplazamientos químicos en los espectros de resonancia magnética nuclear de protón se registran en unidades  (ppm) con respecto a tetrametilsilano, y las constantes de acoplamiento se registran en Hercios (Hz). Los patrones se designan como s: singlete, d: doblete, t: triplete, q: cuarteto, br: ancho.
Las columnas preparativas (2 cm x 25 cm) usadas para la separación preparativa de compuestos quirales, CHIRALPAK AD-H, CHIRALPAK IA, CHIRALPAK IB y CHIRALCEL OJ-H, se fabricaron todas por Daicel Chemical Industries, Ltd.
La “temperatura ambiente” en los siguientes Ejemplos y Ejemplos de Preparación se refiere típicamente a alrededor de 10ºC a alrededor de 35ºC. “%” indica % en peso excepto que se especifique de otro modo.
Ejemplo 1 de preparación
Síntesis de (-)-[(4aR*,8aS*)-8a-(5-amino-2-fluorofenil)-4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-2il]carbamato de terc-butilo
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(1) Síntesis de oxima de 3-buteniloxiacetaldehído
Se añadieron sulfato de hidroxilamina (20,5 g), acetato de sodio (12,8 g) y agua (20 ml) a una disolución de 3buteniloxiacetaldehído (17,8 g; J. Chem. Soc., Perkin Trans. 1, 1999, 3143-3155) en etanol (200 ml). La mezcla se agitó a temperatura ambiente toda la noche, y después se añadió agua. El exceso de etanol se evaporó a presión reducida, y el residuo resultante se extrajo con acetato de etilo. La capa orgánica se lavó con salmuera y se secó sobre sulfato de magnesio anhidro. El disolvente se evaporó a presión reducida, y el residuo se purificó mediante cromatografía en columna en gel de sílice para obtener el compuesto del título (6,20 g).
1H-RMN (400 MHz, CDCl3) δ (ppm): 2,36 (m, 2H), 3,53 (dt, J = 6,6, 8,4 Hz, 2H), 4,10 (d, J = 5,6 Hz, 1H), 4,35 (d, J =4,0 Hz, 1H), 5,10 (m, 2H), 5,82 (m, 1H), 6,91 (t, J = 3,6 Hz, 0,5H), 7,50 (t, J = 5,6 Hz, 0,5H).
(2) Síntesis de 3,3a,4,5-tetrahidro-7H-pirano[3,4-c]isoxazol
Una disolución de hipoclorito de sodio al 5% (122 ml) se añadió gota a gota a una disolución de oxima de 3buteniloxiacetaldehído (5,30 g) en diclorometano (530 ml) bajo enfriamiento con hielo. Después de agitar a la misma temperatura durante dos horas, se añadió tiosulfato de sodio. La capa acuosa se extrajo con diclorometano. Las capas orgánicas se combinaron y se secaron sobre sulfato de magnesio anhidro. El disolvente se evaporó a presión reducida, y el residuo se purificó mediante cromatografía en columna en gel de sílice para obtener el compuesto del título (4,15 g).
1 H-RMN (400 MHz, CDCl3) δ (ppm): 1,79 (ddd, J = 4,4, 12,4, 24,4 Hz, 1H), 2,17 (dd, J = 6,4, 13,2 Hz, 1H), 3,40 (ddd, J = 6,4, 11,2, 22,0 Hz, 1H), 3,50 (dt, J = 2,0, 12,4 Hz, 1H), 3,80 (dd, J = 8,0, 11,6 Hz, 1H), 4,06 (dd, 4,4, 12,8 Hz, 1H), 4,12 (dd, J = 1,2, 13,6 Hz, 1H), 4,63 (dd, J = 8,4, 10,4 Hz, 1H), 4,70 (d, J = 13,6 Hz, 1H).
(3) Síntesis de (±)-(3aR*,7aS*)-7a-(2-fluorofenil)hexahidropirano[3,4-c]isoxazol
Se disolvió 2-bromofluorobenceno (1,85 g) en tolueno (30 ml), y se añadió tetrahidrofurano (10 ml). Se añadió nbutil-litio (2,73 M; 3,68 ml) gota a gota a –78ºC. Se preparó 2-fluorofenil-litio agitando a la misma temperatura durante una hora. Se añadió un complejo de trifluoruro de boro-éter (1,26 ml) a una disolución de 3,3a,4,5-tetrahidro7H-pirano[3,4-c]isoxazol (630 mg) en tolueno (70 ml) a -78ºC. Después de agitar a la misma temperatura durante 10 minutos, se añadió 2-fluorofenil-litio preparado anteriormente a la mezcla de reacción a través de una cánula. Después de agitar a la misma temperatura durante una hora, se añadió una disolución de cloruro de amonio. La mezcla de reacción se devolvió a la temperatura ambiente, y la capa acuosa se extrajo con acetato de etilo. La capa orgánica se lavó con salmuera y se secó sobre sulfato de magnesio anhidro. El disolvente se evaporó a presión reducida, y el residuo se purificó mediante cromatografía en columna en gel de sílice para obtener el compuesto del título (1,26 g).
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ESI-MS; m/z 224 [M+ +H].
1H-RMN (400 MHz, CDCl3 ) δ (ppm): 1,83 (m, 2H), 3,09 (m, 1H), 3,64 (m, 1H), 3,68 (ddt, J = 1,2, 3,2, 11,6 Hz, 1H), 3,73 (d, J = 6,8 Hz, 1H), 3,78 (d, J = 12,8 Hz, 1H) 4,04 (m, 1H), 4,10 (dd, J = 1,6, 12,4 Hz, 1H), 6,32 (s, 1H), 7,04 (ddd, J = 1,2, 8,0, 12,4 Hz, 1H), 7,16 (dt, J = 1,6, 7,6 Hz, 1H), 7,28 (m, 1H), 7,93 (dt, J = 1,6, 8,4 Hz, 1H).
(4) Síntesis de (±)-[(3S*,4R*)-3-amino-3-(2-fluorofenil)tetrahidropiran-4-il]metanol
Se añadió cinc (11,6 g) a una disolución de (±)-(3aR*,7aS*)-7a-(2-fluorofenil)hexahidropirano[3,4-c]isoxazol (3,95 g) en ácido acético (78,4 ml), y la mezcla se agitó a temperatura ambiente toda la noche. La materia insoluble se eliminó mediante filtración a través de celita, y el disolvente se evaporó a presión reducida. Se añadió una disolución 0,5 N de hidróxido de sodio enfriada con hielo al residuo. La capa acuosa se extrajo con acetato de etilo y una disolución mixta de acetato de etilo y tetrahidrofurano. Las capas orgánicas se combinaron y se lavaron con salmuera y después se secaron sobre sulfato de magnesio anhidro. El disolvente se evaporó a presión reducida, y el residuo se purificó mediante cromatografía en columna en gel de sílice para obtener el compuesto del título (3,45 g).
1H-RMN (400 MHz, CDCl3) δ (ppm): 1,61 (m, 1H), 2,28 (m, 2H), 3,35 (dd, J = 2,8, 11,6 Hz, 2H), 3,55 (dd, J = 1,6, 11,6 Hz, 1H), 3,63 (m, 1H), 4,16 (m, 2H), 7,06 (ddd, J = 1,2, 8,0, 12,8 Hz, 1H), 7,20 (dt, J = 1,6, 8,0 Hz, 1H), 7,31 (m, 1H), 7,64 (dt, J = 2,0, 8,0 Hz, 1H).
(5) Síntesis de ácido (±)-9H-fluoren-9-ilmetil({[(3S*,4R*)-3-(2-fluorofenil)-4-(hidroximetil)tetrahidro-2H-piran-3il]amino}carbonotioil)carbámico
Se añadió isotiocianato de fluorenilmetiloxicarbonilo (938 mg) a una disolución de (±)-[(3S*,4R*)-3-amino-3-(2fluorofenil)tetrahidropiran-4-il]metanol (683 mg) en diclorometano (20 ml). La mezcla se agitó a temperatura ambiente toda la noche, y después el disolvente se evaporó a presión reducida a temperatura ambiente o menor. El residuo se purificó mediante cromatografía en columna en gel de sílice para obtener el compuesto del título (1,57 g).
ESI-MS; m/z 529 [M++Na].
1H-RMN (400 MHz, CDCl3 ) δ (ppm): 1,67 (m, 1H), 1,93 (m, 2H), 3,65 (m, 4H), 4,13 (m, 2H), 4,27 (t, J = 6,4 Hz, 1H), 4,55 (m, 2H), 7,02 (dd, J = 4,4, 12,8 Hz, 1H), 7,16 (t, J = 8,0 Hz, 1H), 7,28 (m, 1H), 7,35 (t, J = 7,2 Hz, 2H), 7,44 (t, J = 7,2 Hz, 2H), 7,58 (d, J = 7,6 Hz, 2H), 7,59 (m, 1H), 7,79 (d, J = 8,0 Hz, 2H), 7,93 (s, 1H), 10,67 (s, 1H).
(6) Síntesis de (±)-(4R*,4aS*)-8a-(2-fluorofenil)-4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-2-ilamina
Se añadió ácido clorhídrico concentrado (3,00 ml) a una disolución de ácido (±)-9H-fluoren-9-ilmetil({[(3S*,4R*)-3-(2fluorofenil)-4-(hidroximetil)tetrahidro-2H-piran-3-il]amino}carbonotioil)carbámico (8,00 g) en metanol (200 ml), y la mezcla se calentó a reflujo durante tres horas. La disolución de la reacción se enfrió hasta la temperatura ambiente, y el disolvente se evaporó a presión reducida. Se añadió acetonitrilo (200 ml) al residuo, y se añadió piperidina (40 ml) gota a gota en un baño de agua. La mezcla se agitó a temperatura ambiente durante dos horas, y después el disolvente se evaporó a presión reducida. El residuo se purificó mediante NH-cromatografía en columna en gel de sílice para obtener un producto bruto. El producto bruto resultante se purificó adicionalmente mediante cromatografía en columna en gel de sílice para obtener el compuesto del título (3,96 g).
ESI-MS; m/z 267 [M+ +H].
1H-RMN (400 MHz, CDCl3) δ (ppm): 1,43 (d, J = 17,0 Hz, 1H), 2,12 (m, 1H), 2,61 (d, J = 15,0 Hz, 1H), 2,91 (m, 1H), 2,96 (dd, J = 4,5, 15,5 Hz, 1H), 3,68 (t, J = 15,5 Hz, 1H), 3,76 (d, J = 14,0 Hz, 1H), 4,09 (m, 2H), 4,58 (s a, 2H), 7,03 (dd, J = 10,0, 16,0 Hz, 1H), 7,12 (t, J = 10,0 Hz, 1H), 7,25 (m, 1H), 7,36 (dt, J = 2,5, 10,0 Hz, 1H).
(7) Síntesis de (±)-[(4R*,4aS*)-8a-(2-fluoro-5-nitrofenil)-4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-2il]carbamato de terc-butilo
Se disolvió (±)-(4R*,4aS*)-8a-(2-fluorofenil)-4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-2-ilamina obtenida en el Ejemplo 1-(6) de preparación (3,96 g) en ácido sulfúrico concentrado (20 ml), y se añadió ácido nítrico fumante (gravedad específica: 1,53; 731 l) gota a gota en un baño de hielo. Después de agitar a la misma temperatura durante dos horas, la mezcla de reacción se vertió cuidadosamente en hielo. La capa acuosa se neutralizó con una disolución de bicarbonato de sodio y una disolución de hidróxido de sodio, seguido de extracción con acetato de etilo. La capa orgánica se lavó con salmuera y se secó sobre sulfato de magnesio anhidro. El agente secante se eliminó mediante filtración, y el filtrado se concentró a presión reducida para obtener un residuo. Se añadió tetrahidrofurano (200 ml) al residuo, y después se añadieron secuencialmente trietilamina (10,3 ml) y dicarbonato de di-terc-butilo (4,85 g), seguido de agitación a temperatura ambiente toda la noche. El disolvente se evaporó a presión reducida, y el residuo se purificó mediante cromatografía en columna en gel de sílice para obtener el compuesto del título (5,30 g).
ESI-MS; m/z 41,2 [M++H].
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1H-RMN (400 MHz, CDCl3) δ (ppm): 1,53 (s, 9H), 1,55 (m, 1H), 2,21 (m, 1H), 2,62 (dd, J = 3,2, 12,8 Hz, 1H), 2,85 (dd, J = 2,8, 13,2 Hz, 1H), 3,00 (m, 1H), 3,67 (dt, J = 2,4, 12,0 Hz, 1H), 3,74 (d, J = 11,2 Hz, 1H), 3,97 (dd, J = 2,4, 11,6 Hz, 1H), 4,12 (m, 1H), 7,25 (m, 1H), 8,22 (m, 2H).

(8)

Síntesis de (±)-[(4R*,4aS*)-8a-(5-amino-2-fluorofenil)-4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-2il]carbamato de terc-butilo

Se añadió una disolución saturada de cloruro de amonio (13,2 ml) a una disolución de (±)-[(4R*,4aS*)-8a-(2-fluoro-5nitrofenil)-4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-2-il]carbamato de terc-butilo obtenido en el Ejemplo 1

(7)

de preparación (5,30 g) en etanol (132 ml). Se añadió polvo de hierro (5,76 g) a la mezcla de reacción, seguido de calentamiento a reflujo durante 30 minutos. La mezcla de reacción se enfrió hasta la temperatura ambiente, y la materia insoluble se filtró a través de celita. El filtrado se evaporó a presión reducida. El residuo se purificó mediante NH-cromatografía en columna en gel de sílice para obtener el compuesto del título (4,56 g).

1H-RMN (400 MHz, CDCl3) δ (ppm): 1,53 (s, 9H), 1,53 (m, 1H), 2,23 (m, 1H), 2,54 (dd, J = 2,4, 12,4 Hz, 1H), 2,98 (dd, J = 4,0, 12,4 Hz, 1H), 3,03 (m, 1H), 3,66 (m, 2H), 4,07 (dd, J = 1,6, 12,4 Hz, 1H), 4,12 (m, 1H), 6,57 (m, 2H), 6,86 (dd, J = 8,8, 12,4 Hz, 1H).

(9)

Síntesis de (-)-[(4R*,4aS*)-8a-(5-amino-2-fluorofenil)-4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-2il]carbamato de terc-butilo

Se purificó (±)-[(4R*,4aS*)-8a-(5-amino-2-fluorofenil)-4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-2il]carbamato de terc-butilo obtenido en el Ejemplo 1-(8) de preparación (100 mg) mediante CHIRALPAK™ AD-H (fase móvil: hexano:etanol = 8,5:1,5, caudal: 20 ml/min.), y se recogió la fracción con un tiempo de retención de 20,9 a 27,8 minutos para obtener el compuesto del título. Se repitió la misma operación para obtener el compuesto del título (405 mg; >99% ee) a partir del material bruto (1,00 g).
Ejemplo 2 de preparación
Síntesis de ácido 5-fluorometoxipirazin-2-carboxílico
[Fórmula 27] imagen24
(1) Síntesis de 5-fluorometoxipirazin-2-carboxilato de metilo
Se añadieron tolueno-4-sulfonato de fluorometilo (Journal of Labelled Compounds & Radiopharmaceuticals, 46 (6), 555-566; 2003) (344 mg) y carbonato de cesio (824 mg) a una disolución de 5-hidroxipirazin-2-carboxilato de metilo (130 mg) en N,N-dimetilformamida (2,0 ml). La disolución de la reacción se agitó a 70ºC durante cinco horas y 30 minutos, y después se enfrió hasta la temperatura ambiente. Se añadió agua a la disolución de la reacción, seguido de extracción con acetato de etilo. La capa orgánica se concentró a presión reducida. El residuo se purificó mediante NH-cromatografía en columna en gel de sílice para obtener el compuesto del título (18,0 mg).
1H-RMN (400 MHz, CDCl3 ) δ (ppm): 4,03 (s, 3.H), 6,14 (d, J = 51,2 Hz, 2H), 8,42 (d, J = 1. 2 Hz, 1H), 8,94 (d, J = 1,2 Hz, 1H).
(2) Síntesis de ácido 5-fluorometoxipirazin-2-carboxílico
Se añadió trimetilsilanolato de potasio (18,6 mg) a una disolución de 5-fluorometoxipirazin-2-carboxilato de metilo obtenido en el Ejemplo 15-(1) de preparación (18,0 mg) en tetrahidrofurano (1,0 ml). La disolución de la reacción se agitó a temperatura ambiente durante una hora. Se añadieron agua y acetato de etilo a la disolución de la reacción, y la capa orgánica se separó. La capa acuosa se hizo ácida con ácido clorhídrico 1 M, seguido de extracción con acetato de etilo. La capa orgánica se secó sobre sulfato de magnesio anhidro. El agente secante se eliminó mediante filtración, y el filtrado se concentró a presión reducida para obtener un producto bruto del compuesto del título (10,2 mg). El compuesto se usó para la reacción siguiente sin purificación adicional.
1H-RMN (400 MHz, CDCl3) δ (ppm): 6,16 (d, J = 50,8 Hz, 2H), 8,34 (d, J = 1,4 Hz, 1H), 9,05 (d, J = 1,4 Hz, 1H).
Ejemplo 3 de preparación
Síntesis de ácido 5-cianopiridin-2-carboxílico
[Fórmula 28]
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(1) Síntesis de 5-cianopiridin-2-carboxilato de metilo
Una mezcla de 5-bromopiridin-2-carboxilato de metilo (2,8 g) y cianuro de cobre (3,6 g) en NMP (30 ml) se calentó con agitación a 170ºC durante 1,5 horas. Se añadió agua a la disolución de la reacción a temperatura ambiente, y la materia insoluble se eliminó mediante filtración. El filtrado se extrajo con acetato de etilo. El extracto se lavó con salmuera y después se secó sobre sulfato de magnesio anhidro. El agente secante se separó por filtración, y el filtrado se concentró a presión reducida. El producto bruto resultante se purificó mediante cromatografía en columna en gel de sílice para obtener el compuesto del título (920 mg).
1H-RMN (400 MHz, CDCl3) δ (ppm): 4,06 (s, 3H), 8,16 (dd, J = 2,0, 8,0 Hz, 1H), 8,27 (d, J = 8,0 Hz, 1H), 9,01 (d, J = 2,0 Hz, 1H).
(2) Síntesis de ácido 5-cianopiridin-2-carboxílico
Una disolución del compuesto del Ejemplo 3-(1) de preparación (920 mg) y una disolución 5 N de hidróxido de sodio (2,26 ml) en etanol (30 ml) se agitó a temperatura ambiente durante 10 minutos. Se añadió ácido clorhídrico 5 N (5,2 ml) a la disolución de la reacción a temperatura ambiente, seguido de extracción con acetato de etilo. El extracto se secó sobre sulfato de magnesio anhidro. El agente secante se eliminó mediante filtración, y el filtrado se concentró a presión reducida para obtener el compuesto del título (800 mg).
1H-RMN (400 MHz, DMSOd6) δ (ppm): 8,18 (d, J = 8,0 Hz, 1H), 8,51 (dd, J = 2,0, 8,0 Hz, 1H), 9,12-9,18 (m, 1H).
Ejemplo 4 de preparación
Síntesis de ácido 5-difluorometoxipirazin-2-carboxílico
[Fórmula 29] imagen26
(1) Síntesis de 5-difluorometoxipirazin-2-carboxilato de metilo
Se añadieron carbonato de potasio (8,82 g) y clorodifluoroacetato de sodio (6,53 g) a una disolución de 5hidroxipirazin-2-carboxilato de metilo (3,3 g) en DMF (42,8 ml). La disolución de la reacción se agitó a 100ºC durante 30 minutos, y después se añadió cloruro de amonio acuoso saturado, seguido de extracción con acetato de etilo. La capa orgánica se lavó con una disolución de bicarbonato de sodio y con salmuera, y después se secó sobre sulfato de magnesio. El agente secante se eliminó mediante filtración, y después el disolvente se evaporó a presión reducida. El residuo se purificó mediante cromatografía en columna en gel de sílice para obtener el compuesto del título (928 mg).
1H-RMN (400 MHz, CDCl3) δ (ppm): 4,04 (s, 3H), 7,49 (t, J = 71,2 Hz, 1H), 8,47 (d, J = 0,8 Hz, 1H), 8,92 (d, J = 0,8 Hz, 1H).
(2) Síntesis de ácido 5-difluorometoxipirazin-2-carboxílico
Se añadieron agua (1,54 ml) y una disolución 5 N de hidróxido de sodio (492 ml) a una disolución del compuesto obtenido en el Ejemplo 4-(1) de preparación (250 mg) en THF (4,60 ml). La disolución de la reacción se agitó a temperatura ambiente durante cinco minutos, y después se añadió una disolución 2 N de ácido clorhídrico, seguido de extracción con acetato de etilo. La capa orgánica se lavó con salmuera, y después se secó sobre sulfato de magnesio. El agente secante se eliminó mediante filtración, y después el disolvente se concentró a presión reducida para obtener el compuesto del título (200 mg).
1H-RMN (400 MHz, CDCl3) δ (ppm): 7,51 (t, J = 71,2 Hz, 1H), 8,39 (d, J = 1,2 Hz, 1H), 9,04 (d, J = 1,2 Hz, 1H).
Ejemplo 5 de preparación
Síntesis de (-)-[(4aR*,8aS*)-8a-(5-amino-2-trifluorometoxifenil)-4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-2il]carbamato de terc-butilo
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En el Ejemplo 5 de preparación, se usó como material de partida el compuesto obtenido en el Ejemplo 1-(2) de preparación.
En el Ejemplo 5-(1) y (2) de preparación, la síntesis se llevó a cabo según el Ejemplo 1-(3) y (4) de preparación.
(3) Síntesis de 1-benzoil-3-[(3S*,4R*)-4-hidroximetil-3-(2-trifluorometoxifenil)tetrahidropiran-3-il]tiourea
Se añadió isotiocianato de benzoílo (642 l) a una disolución del compuesto obtenido en la etapa anterior (1,26 g) en diclorometano (32,3 ml) a temperatura ambiente, y la mezcla se agitó durante dos horas y 30 minutos. La disolución de la reacción se concentró a presión reducida, y el residuo se purificó mediante cromatografía en columna en gel de sílice para obtener el compuesto del título (1,67 g).
1H-RMN (400 MHz, CDCl3) δ (ppm): 1,29-1,34 (m, 1H), 1,65-1,80 (m, 2H), 3,57-3,91 (m, 4H), 4,14-4,27 (m, 2H), 7,20-7,30 (m, 3H), 7,32-7,38 (m, 1H), 7,50-7,57 (m, 2H), 7,61-7,67 (m, 1H), 7,86-7,92 (m, 1H), 8,92 (s a, 1H).
(4) Síntesis de N-[(4aR*,8aS*)-8a-(2-trifluorometoxifenil)-4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-2il]benzamida
Se añadió ácido clorhídrico concentrado (635 l) a una disolución del compuesto obtenido en la etapa anterior (1,67 g) en metanol (25 ml), y la mezcla se calentó a reflujo a 90ºC durante dos horas y 10 minutos. La disolución de la reacción se devolvió a la temperatura ambiente y se concentró a presión reducida. Se añadió al residuo una disolución de bicarbonato de sodio, seguido de extracción con acetato de etilo. La capa orgánica se secó sobre sulfato de magnesio anhidro. El agente secante se separó por filtración, y el filtrado se concentró a presión reducida para obtener el compuesto del título (1,65 g).
1H-RMN (400 MHz, CDCl3) δ (ppm): 1,53-1,68 (m, 1H), 2,22-2,35 (m, 1H), 2,62-2,71 (m, 1H), 2,91-2,99 (m, 1H), 3,19-3,29 (m, 1H), 3,62-3,78 (m, 2H), 4,07-4,21 (m, 2H), 7,28-7,36 (m, 2H), 7,38-7,47 (m, 3H), 7,48-7,57 (m, 2H), 8,21-8,27 (m, 2H).
(5) Síntesis de (4aR*,8aS*)-8a-(2-trifluorometoxifenil)-4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-2-ilamina
Se añadió DBU (1,28 ml) a una disolución del compuesto obtenido en la etapa anterior (1,65 g) en metanol (100 ml), y la mezcla se calentó a reflujo a 80ºC durante ocho horas y 10 minutos. La disolución de la reacción se devolvió a la temperatura ambiente y se concentró a presión reducida. El residuo se purificó mediante NH-cromatografía en columna en gel de sílice para obtener el compuesto del título (870 mg).
1H-RMN (400 MHz, CDCl3) δ (ppm): 1,40-1,50 (m, 1H), 2,02-2,16 (m, 1H), 2,61-2,70 (m, 1H), 2,87-3,01 (m, 2H), 3,60-3,75 (m, 2H), 4,03-4,15 (m, 2H), 4,51 (s a, 2H), 7,21-7,34 (m, 3H), 7,48-7,52 (m, 1H).
En el Ejemplo 5-(6), (7) y (8) de preparación, la síntesis se llevó a cabo según el Ejemplo 1-(7) y (8) de preparación.
(9) Síntesis de (-)-[(4aR*,8aS*)-8a-(5-amino-2-trifluorometoxifenil)-4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen2-il]carbamato de terc-butilo
El compuesto obtenido en la etapa anterior (12 mg) se purificó mediante CHIRALPAK™ AD-H (fase móvil: hexano:etanol = 8:2, caudal: 10 ml/min.), y la fracción con un tiempo de retención de 15 a 20 minutos se recogió
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para obtener el compuesto del título. Esta operación se repitió para obtener el compuesto del título (112 mg; >99% ee) a partir de 240 mg del racemato.
1H-RMN (400 MHz, CDCl3) δ (ppm): 1,53 (s, 9H), 1,54-1,60 (m, 1H), 2,13-2,27 (m, 1H), 2,51-2,60 (m, 1H), 2,90-2,96 (m, 1H), 3,03-3,12 (m, 1H), 3,58-3,67 (m, 2H), 3,80 (s a, 2H), 4,05-4,17 (m, 2H), 6,60 (dd, J = 8,8, 2,8 Hz, 1H), 6,67 (d, J = 2,8 Hz, 1H), 7,06-7,11 (m, 1H).
Ejemplo 6 de preparación
Síntesis de (-)-[(4aR*,6S*,8aS*)-8a-(5-amino-2-fluorofenil)-6-metil-4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen2-il]carbamato de terc-butilo
[Fórmula 31] imagen28
(1) Síntesis de 4-(2,2-dietoxi-etoxi)-1-penteno
Se añadió hidruro de sodio al 60% (916 mg) a una disolución de 4-penten-2-ol (1,8 ml) en dimetilformamida (40 ml) a 0ºC, seguido de agitación durante 30 minutos. Después de calentar hasta la temperatura ambiente, se añadió acetal dietílico de bromoacetaldehído (2,99 ml) a la disolución de la reacción, y la mezcla se calentó durante cinco horas. Se añadió hielo a la disolución de la reacción, seguido de extracción con éter dietílico. La capa orgánica se concentró a presión reducida. El residuo se purificó mediante cromatografía en columna en gel de sílice para obtener el compuesto del título (1,95 g). 20 (2005)).
Specifically, the compound (1-2) can be obtained by having a base act on the compound (1-1), and then reacting the compound with N-phenyltrifluoromethanesulfonimide or trifluoromethanesulfonic anhydride, for example. This reaction can be carried out by having one or more equivalents of a base act on the compound (1-1) in an organic solvent such as ether, tetrahydrofuran, 1,4-dioxane,
1,2-dimethoxyethane, dichloromethane, 1,2-dichloroethane, benzene or toluene, for example. Examples of the base used include sodium hydride, LDA (lithium diisopropylamide), lithium bis (trimethylsilyl) amide, diisopropylethylamine, pyridine and 2,6-lutidine. The reaction time is not particularly limited, and is usually 5 minutes to 24 hours, and preferably 5 minutes to 12 hours. The reaction temperature is usually -100 ° C to room temperature, and more preferably -78 ° C to room temperature.
30 1-2. Stage 1-2:
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This step is a step to obtain a compound (1-3) by coupling reaction of the compound (1-2) using a transition metal.
This reaction can be carried out under the conditions commonly used in coupling reaction using a transition metal (such as the Suzuki coupling reaction or the Stille coupling reaction).
Examples of the reaction using an organoboro reagent as an organometallic compound include reactions in documents such as Tetrahedron: Asymmetry 16 (2005) 2, 529-539 and Org. Lett. 6 (2004) 2, 277
279. Examples of the reaction using an organotin reagent include reaction in a document such as Tetrahedron 61 (2005) 16, 4129-4140. Examples of the reaction using an organocinc reagent as an organometallic compound include reaction in a document such as Tetrahedron 61 (2005) 16, 4129-4140. The organometallic catalyst used in this reaction is not particularly limited. Preferable examples of the organometallic catalyst include tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), [1,1'-bis (diphenylphosphino) ferrocene dichloride] palladium (II), bis (tert-butylphosphine) palladium (0), palladium (II) acetate and [1,3bis (diphenylphosphino) propane] nickel (II). The amount of the organometallic catalyst used is about 0.001 to 0.1 equivalents with respect to the raw material. The organometallic compound is not particularly limited. Preferable examples of the organometallic compound include organotin reagents such as aryltri-n-butyltin, and organoboro reagents such as arylboronic acid. The amount of the organometallic compound used is one to five equivalents with respect to the raw material. The solvent used in this reaction is not particularly limited as long as it does not inhibit the reaction. Preferable examples of the solvent include benzene, toluene, xylene, N, N-dimethylformamide, 1-methyl-2-pyrrolidone, tetrahydrofuran, 1,4-dioxane, acetonitrile and propionitrile. The reaction temperature is not particularly limited, and is for example usually the temperature cooled with ice to the reflux temperature of the solvent, and preferably the ambient temperature to the reflux temperature of the solvent. The reaction time is not particularly limited, and is usually 0.5 to 48 hours, and preferably 0.5 to 24 hours.
A more preferable result, such as improved performance, can be achieved by carrying out this reaction in the presence of a base. Such a base is not particularly limited. Preferable examples of the base include bases such as sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, and its solutions, and triethylamine.
1-3. Stage 1-3:
This stage is a step to obtain an alcoholic compound (1-4) by subjecting the ester compound (1-3) to a reduction reaction. The alcoholic compound (1-4) can be obtained from the ester compound (1-3) by a method known to a person skilled in the art.
Examples of the reducing agent used in the reaction include lithium aluminum hydride, lithium borohydride and diisobutylaluminum hydride. The reaction temperature is not particularly limited, and is usually -78 ° C to the reflux temperature of the solvent, and preferably -78 ° C to room temperature. The solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction and allows the starting material to dissolve therein to some extent. Preferable examples of the solvent include tetrahydrofuran, diethyl ether, toluene and dichloromethane.
1-4. Stage 1-4:
This step is a step to obtain a compound (1-5) by converting the hydroxyl group of the compound (1-4) into a leaving group.
Examples of the leaving group include halogen atoms (such as a chlorine atom, a bromine atom and an iodine atom) and sulfonyloxy groups such as a methanesulfonyloxy group, a p-toluenesulfonyloxy group and a trifluoromethanesulfonyloxy group.
The reaction can be carried out under the same conditions as usually used in a reaction of converting a hydroxyl group into such leaving group. When the leaving group is a halogen atom, for example, the compound (1-5) can be prepared by reacting the compound (1-4) with, for example, thionyl chloride, thionyl bromide, phosphorus tribromide or tetrahalogenomethane -triphenylphosphine. The solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction and allows the starting material to dissolve therein to some extent. Preferable examples of the solvent include benzene, toluene, xylene, dichloromethane and chloroform. The reaction temperature is usually -78 ° C to the reflux temperature of the solvent, and preferably ice-cooled temperature to the reflux temperature of the solvent. The reaction time is not particularly limited, and is usually 5 minutes to 48 hours, and preferably 5 minutes to 12 hours.
When the leaving group is a sulfonyloxy group, the compound (1-5) can be prepared by reacting the compound (1-4) with, for example, methanesulfonyl chloride, p-toluenesulfonyl chloride or trifluoromethanesulfonic anhydride.
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The solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction and allows the starting material to dissolve therein to some extent. Preferable examples of the solvent include tetrahydrofuran, toluene, xylene, dichloromethane, chloroform and N, N-dimethylformamide. The reaction temperature is usually -78 ° C to the reflux temperature of the solvent, and preferably -78 ° C to room temperature. A favorable result, such as improved performance, can be achieved by adding a base. The base used is not particularly limited as long as it does not inhibit the reaction. Preferable examples of the base include sodium carbonate, potassium carbonate, triethylamine, pyridine and diisopropylethylamine.
1-5. Stage 1-5:
This stage is a step to obtain a compound (1-6) from the compound (1-5). The thiourea compound (16) can be obtained from the compound (1-5) by a method known to a person skilled in the art.
Specifically, the compound (1-6) can be obtained by reacting the compound (1-5) with thiourea in a solvent, for example. This reaction can be carried out by having one or more thiourea equivalents act on the compound (1-5) in an organic solvent such as methanol, ethanol, 1-propanol, 2-propanol, 1butanol, tetrahydrofuran, 1,4- dioxane or N, N-dimethylformamide, for example. The reaction time is not particularly limited, and is usually 5 minutes to 24 hours, and preferably 5 minutes to 12 hours. The reaction temperature is usually 0 ° C to 150 ° C, and more preferably room temperature to 100 ° C.
1-6. Stage 1-6:
This step is a method of obtaining a compound (1-7) by cycling a compound (1-6) with an acid.
This reaction is not particularly limited, as long as it does not inhibit the reaction and allows the starting material to dissolve therein to some extent. For example, the reaction can be carried out by having an equivalent to a large excess of an appropriate acid act on the compound in the presence or absence of a solvent such as benzene, toluene or dichloromethane. Additionally, an acid can also be used as a solvent. Examples of the acid used include sulfuric acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid and mixtures thereof. The reaction time is not particularly limited, and is usually 1 to 72 hours, and preferably 1 to 48 hours. The reaction temperature is usually ice-cooled temperature to the reflux temperature of the solvent.
The compound (1-7), in which both R1 and R2 are hydrogen atoms, can be obtained by the above reaction.
The compound (1-7), in which both R1 and R2 are hydrogen atoms, can be converted into the compound (1-7), in which at least one of R1 and R2 is substituted with a substituent, by reaction additional with a corresponding or similar halide compound such as a C1-6 alkyl halide, a C1-6 alkylcarbonyl halide, a C6-14 aryl halide-carbonyl, a C1-6 alkyl sulfonyl halide, a halide C6-14-sulfonyl aryl, a 3-10 membered carbocyclic halide or a 5-10 membered heterocyclic halide.
2. General Preparation Method 2:
[Formula 9] image9
In the formula, Ring A, R3, R4, R5, R6, Y, and Z are as defined above. 10
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The General Preparation Method 2 is a method for preparing a compound of the general formula (1-4) which is a synthetic intermediate of the compound (I) according to the present invention from a compound (2-1) as the raw material a through multiple stages from Stage 2-1 to Stage 2-3.
The compound (2-1) can be a commercially available product used as such, it can also be prepared from a commercially available product by a method known to a person skilled in the art, and can be further prepared by a method described in Preparation Examples, within the Examples.
2-1. Stage 2-1:
This stage is a stage to obtain a compound (2-2) from the compound (2-1). This reaction can be carried out under the same conditions as those commonly used in the synthesis reaction of a compound (2-2) from a carbonyl compound (such as the conditions described in J. Org. Chem., 47, 3597-3607 (1982)).
2-2. Stage 2-2:
This step is a step to synthesize a compound (2-3) from the compound (2-2) as a raw material using a method described in the previous preparation method (Step 1-2).
2-3. Stage 2-3:
This stage is a step to obtain the alcoholic compound (1-4) by subjecting the aldehyde compound (2-3) to a reduction reaction.
The alcoholic compound (1-4) can be obtained from the aldehyde compound (2-3) by a method known to a person skilled in the art. Examples of the reducing agent used in the reaction include sodium borohydride, sodium cyanoborohydride and sodium triacetoxyborohydride. The reaction temperature is not particularly limited, and is usually -78 ° C at the reflux temperature of the solvent, and preferably -20 ° C to room temperature. The solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction and allows the starting material to dissolve therein to a certain degree. Preferable examples of the solvent include methanol, ethanol, tetrahydrofuran, ether, toluene and dichloromethane.
3. General Preparation Method 3: image10
In the formula, L1 represents a single bond or a C1-6 alkyl group and Ring A, R1, R2, R3, R4, R5, R6, X, Y, Z and Ring B are as defined above.
The General Preparation Method 3 is a method for preparing the compound of the general formula (I) according to the present invention, in which L is a -NHCO-C1-6 alkyl group, and R1 and R2 are hydrogen atoms, from a compound (3-1) as raw material through multiple stages from Stage 3-1 to Stage 3-4.
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The compound (3-1) can be prepared from a commercially available product by General Preparation Method 1, General Preparation Method 2, General Preparation Method 4, or a combination of these three methods, and can also be prepared by a method described in the Preparation Examples within the Examples. Compounds (3-4) and (3-5) can be commercially available products used directly, can also be prepared from a commercially available product by a method known to a person skilled in the art, and can also be prepared by a method described in the Preparation Examples within the Examples.
3-1. Stage 3-1:
This step is a step to obtain a compound (3-2) t-butoxycarbonylating the amino group of the compound (3-1) when R1 and R2 are both hydrogen.
The reaction can be carried out under the same conditions as those generally used in the t-butoxycarbonylation of an amino compound, such as the conditions described in a document such as TW Green and PGM Wuts, "Protective Groups in Organic Chemistry, Second Edition", John Wiley & Sons (1991), p. 327-330. The compound (3-2) can be obtained by reacting the compound (3-1) with di-tert-butyl dicarbonate using triethylamine as a base in a solvent such as, for example, tetrahydrofuran.
3-2 Stage 3-2:
This stage is a stage to obtain a compound (3-3) from the compound (3-2).
The compound (3-3) is synthesized by reducing the nitro compound (3-2) by a synthesis method known to a person skilled in the art. Examples of the method include reduction by catalytic hydrogenation using a noble metal catalyst such as Raney nickel, palladium, ruthenium, rhodium or platinum. In this case, it is preferable, for example, the reduction reaction with iron under neutral conditions using ammonium chloride.
3-3. Stage 3-3:
This step is a step to obtain a compound (3-6) by condensing the compound (3-3) with the compound (3-4) using a condensing agent. Alternatively, this step is a step to obtain a compound (3-6) by condensing the compound (3-3) with the compound (3-5) by acylation reaction.
The condensation reaction of the compound (3-3) with the compound (3-4) using a condensing agent can be carried out under the same conditions as those commonly used and described in the following documents. Examples of the known method include those in Rosowsky, A .; Forsch, RA; Moran, R. G; Freisheim, JH; J. Med. Chem., 34 (1), 227-234 (1991), Brzostwska, M .; Brossi, A .; Flippen-Anderson, JL; Heterocycles, 32 (10), 1969-1972 (1991), and Romero, DL; Morge, RA; Biles, C .; Berrios-Pena, N .; May, PD; Palmer, JR; Johnson, PD; Smith, HW; Busso, M .; Tan, C.-K .; Voorman, RL; Reusser, F .; Althaus, IW; Downey, KM; So, A. G; Resnick, L .; Tarpley, W. G, Aristoff, PA; J. Med. Chem., 37 (7), 999-1014 (1994).
The compound (3-3) can be a free form or a salt.
The solvent in this reaction is not particularly limited as long as it does not inhibit the reaction. Examples of the solvent include tetrahydrofuran, 1,4-dioxane, ethyl acetate, methyl acetate, dichloromethane, chloroform, N, N-dimethylformamide, toluene and xylene. Examples of the condensing agent include CDI (N, N'-carbonyldiimidazole), Bop (1H-1,2,3-benzotriazol-1-yloxy (tri (dimethylamino)) phosphonium hexafluorophosphate), WSC (1-ethyl hydrochloride -3- (3dimethylaminopropyl) carbodiimide), DCC (N, N-dicyclohexylcarbodiimide), diethylphosphoryl cyanide, PyBOP (benzotriazol-1-yloxytris (pyrrolidine) phosphonium hexafluorophosphate) and EDC · HCl (1-hydrochloride 3dimethylaminopropyl) carbodiimide). An equivalent to a large excess of the compound (3-4) is used with respect to the compound (3-3). When necessary, an equivalent can be added to a large excess of an organic base such as triethylamine.
The reaction time is not particularly limited, and is usually 0.5 to 48 hours, and preferably 0.5 to 24 hours. The reaction temperature varies according to the raw material used, the solvent, and the like, and is not particularly limited. The ice-cooled temperature is preferable to the reflux temperature of the solvent.
3-4. Stage 3-4:
This step is a step to obtain the compound (Ia) by deprotection reaction of the tbutoxycarbonyl group of the compound (3-6).
The reaction can be carried out under the same conditions as those generally used in a deprotection reaction of a t-butoxycarbonyl group, such as the conditions described in a document such as TW Green and PGM Wuts, "Protective Groups in Organic Chemistry, Second Edition ”, John Wiley & Sons (1991), p. 327-330. The compound (Ia) can be obtained by reacting trifluoroacetic acid with the compound (3-6) in a solvent such as, for example, dichloromethane.
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The compound of the formula (I) according to the present invention, wherein at least one of R1 and R2 is a C1-6 alkyl group which may have 1 to 3 substituents selected from the Substituent Group , a C1-6 alkyl group -carbonyl which may have 1 to 3 substituents selected from the Substituent Group , an aryl C6-14-carbonyl group which may have 1 to 3 substituents selected from the Substituent Group , a C 1-6 alkyl-sulfonyl group which may have 1 to 3 substituents selected from the Substituent Group , an aryl C6-14-sulfonyl group which may have 1 to 3 substituents selected from the Substituent Group , a hydrocarbon ring group of C3-8 which may have 1 to 3 substituents selected from the Substituent Group , or a 5-10 membered heterocyclic group that may have 1 to 3 substituents selected from the Substituent Group , can be obtained by further reacting the compound (Ia) obtained in Method 3 of General Preparation with a comp corresponding or similar halide position such as a C1-6 alkyl halide. Alternatively, the compound of the formula (I) according to the present invention, wherein L is -NRLCO- (in which RL is a C1-6 alkyl group which may have 1 to 3 substituents selected from the Substituent Group ) , can be obtained by further reacting the compound (Ia) obtained in General Preparation Method 3 with a corresponding or similar halide compound such as a C1-6 alkyl halide.
The compound of the formula (I) according to the present invention, wherein L is -NRLSO2- (in which RL is a hydrogen atom), can be obtained using a corresponding sulfonyl compound or a sulfonyl halide compound instead of compound (3-4) or (3-5) used in General Preparation Method 3. The compound of the formula (I) according to the present invention, in which L is -NRLSO2- (in which RL is a C1-6 alkyl group which may have 1 to 3 substituents selected from the Substituent Group ), can be obtained by further reacting this compound with a corresponding or similar halide compound such as a C1-6 alkyl halide.
In Step 3-3 of General Preparation Method 3, compound (3-6) can also be prepared from compound (3-3) and compound (3-4) by a method described in the following alternative method (1 or 2).
Alternative method (I):
The compound (3-6) can be obtained by converting the compound (3-4) into a mixed acid anhydride and then reacting the mixed acid anhydride with the compound (3-3). The mixed acid anhydride can be synthesized by a means known to the person skilled in the art. The synthesis is carried out by reacting the compound (3-4) with a chloroformate, such as ethyl chloroformate, in the presence of a base, such as, for example, triethylamine. One to two equivalents of the chloroformate and the base are used with respect to the compound (3-4). The reaction temperature is -30 ° C to room temperature, and preferably -20 ° C to room temperature.
The condensation step of the mixed acid anhydride with the compound (3-3) is carried out by reacting the mixed acid anhydride with the compound (3-3) in a solvent such as, for example, dichloromethane, tetrahydrofuran or N , N-dimethylformamide. An equivalent to a large excess of compound (3-3) is used with respect to mixed acid anhydride.
The reaction time is not particularly limited, and is usually 0.5 to 48 hours, and preferably 0.5 to 12 hours. The reaction temperature is -20 ° C to 50 ° C, and preferably -20 ° C to room temperature.
Alternative method (2):
The compound (3-6) can be obtained by converting the compound (3-4) into an active ester, and then reacting the active ester with the compound (3-3). The step to obtain the active ester is carried out by reacting the compound (3-4) with an active ester synthesis reagent in a solvent such as 1,4-dioxane, tetrahydrofuran or N, N-dimethylformamide in the presence of a condensing agent such as, for example, DCC. Examples of the active ester synthesis reagent include N-hydroxysuccinimide. One to 1.5 equivalents of the active ester synthesis reagent and the condensing agent are used with respect to the compound (3-4). The reaction time is not particularly limited, and is usually 0.5 to 48 hours, and preferably 0.5 to 24 hours.
The reaction temperature is -20 ° C to 50 ° C, and preferably -20 ° C to room temperature.
The condensation step of the active ester with the compound (3-3) is carried out by reacting the active ester with the compound (3-3) in a solvent such as, for example, dichloromethane, tetrahydrofuran or N, N-dimethylformamide. An equivalent to a large excess of the compound (3-3) is used with respect to the active ester. The reaction time is not particularly limited, and is usually 0.5 to 48 hours, and preferably 0.5 to 24 hours. The reaction temperature is -20 ° C to 50 ° C, and preferably -20 ° C to room temperature.
In this acylation reaction, the compound (3-6) can be obtained from the compounds (3-3) and (3-5) by a method known to a person skilled in the art.
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Examples of the base used in the reaction include triethylamine, pyridine, potassium carbonate and diisopropylethylamine. The reaction temperature is not particularly limited, and is usually -78 ° C to the reflux temperature of the solvent, and preferably -20 ° C to room temperature. The solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction and allows the starting material to dissolve therein to some extent. Preferable examples of the solvent include tetrahydrofuran, ether, toluene and dichloromethane.
4. General Preparation Method 4: image11
In the formula, Ring A, R1, R2, R3, R4, R5, R6, X, Y and Z are as defined above.
The General Preparation Method 4 is a method for preparing a compound of the general formula (3-1) which is a synthetic intermediate of the compound according to the present invention from a compound (4-1) as a raw material through Stage 4-1.
The compound (4-1) can be prepared from a commercially available product by General Preparation Method 1, General Preparation Method 2, General Preparation Method 5, or a combination of
These methods, and can also be prepared by a method described in the Preparation Examples within the Examples.
4-1. Stage 4-1:
This step is a step to obtain the compound (3-1) by nitration reaction of the compound (4-1). In this nitration reaction, the compound (3-1) can be obtained from the compound (4-1) by a method
20 known to a person skilled in the art. Examples of the nitrating agent used in the reaction include potassium nitrate / concentrated sulfuric acid, and smoking nitric acid / acetic anhydride. The reaction temperature is not particularly limited, and is usually -20 ° C to room temperature.
5. General Preparation Method 5:
[Formula 12]
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In the formula, Prt represents a protecting group such as a benzoyl group, an acetyl group or a 9-fluoroethylmethylcarbonyl group (Fmoc group), and Ring A, R3, R4, R5, R6, Y and Z are as defined above.
The General Preparation Method 5 is a method for preparing a compound (1-7) which is a synthetic intermediate 5 of the compound (I) according to the present invention from a compound (5-1) as a raw material through multiple stages from Stage 5-1 to Stage 5-7.
The compound (5-1) can be prepared from a commercially available product by a method known to a person skilled in the art, and can also be prepared by a method described in the Preparation Examples within the Examples.
10 5-1. Stage 5-1:
This stage is a step to obtain a compound (5-2) by oxidizing the compound (5-1).
The reaction at this stage can be carried out under the same conditions as those commonly used in the oximeation reaction of a carbonyl compound, such as the conditions described in Org. Lett. 9 (2007) 5, 753-756, Tetrahedron: Asymmetry 5 (1994) 6, 1018-1028 and Tetrahedron 54 (1998) 22, 5869-5882.
Specifically, the compound (5-2) can be obtained by reacting the compound (5-1) with hydroxylamine or a hydroxylamine salt (such as hydroxylamine hydrochloride or hydroxylamine sulfate) in the presence of a base or in the absence of a base, for example.
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The solvent used in this reaction is not particularly limited as long as it does not inhibit the reaction. Preferable examples of the solvent include organic solvents such as ethanol, methanol, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and dichloromethane, and mixtures of these solvents and water. Examples of the base used include sodium acetate, pyridine, sodium hydroxide, cesium hydroxide, barium hydroxide and 2,6-lutidine. The reaction time is not particularly limited, and is usually 5 minutes to 24 hours, and preferably 5 minutes to 12 hours. The reaction temperature is usually -20 ° C to the reflux temperature of the solvent, and more preferably 0 ° C to the reflux temperature of the solvent.
5-2. Stage 5-2:
This step is a step to obtain a compound (5-3) by converting the compound (5-2) into a nitrile oxide derivative, and carrying out a dipole 1.3 cycloaddition reaction with the olefinic moiety in the same molecule .
The reaction at this stage can be carried out under the same conditions as those commonly used in a 1,3-dipole cycloaddition reaction, such as the conditions described in a document such as Org. Lett. 9 (2007) 5, 753-756, Tetrahedron: Asymmetry 5 (1994) 6, 1018-1028 and Tetrahedron 54 (1998) 22, 5869-5882. Examples of the reagent for converting the oxidic compound to nitrile oxide include N-chlorosuccinimide and sodium hypochlorite. The solvent used in this reaction is not particularly limited as long as it does not inhibit the reaction. Preferable examples of the solvent include dichloromethane, chloroform, benzene, toluene, xylene, N, N-dimethylformamide, tetrahydrofuran and 1,4-dioxane. The reaction temperature is not particularly limited, and it is usually the temperature of cooling with ice to the reflux temperature of the solvent. The reaction time is not particularly limited, and is usually 0.5 to 48 hours, and preferably 0.5 to 24 hours.
A more preferable result, such as improved performance, can be achieved by carrying out this reaction in the presence of a base. Such a base is not particularly limited. Examples of the base include bases such as sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate and its solutions, and triethylamine and pyridine.
5-3. Stage 5-3:
This step is a step to obtain a compound (5-4) by adding reaction of an aryl lithium reagent (including heterocyclic) or a Grignard reagent (including heterocyclic) with the compound (5-3).
The reaction at this stage can be carried out under the same conditions as described in J. Am. Chem. Soc. 2005, 127, 5376-5383, Bull. Chem. Soc. Jpn., 66, 2730-2737 (1993) and SYNLETT. 2004, no. 8, p. 1409-1413, for example.
The aryl lithium reagent (including heterocyclic) or Grignard reagent (including heterocyclic) can be prepared by a method known to a person skilled in the art. Specifically, an aryl (including heterocyclic) -lithium reagent or a corresponding aryl (including heterocyclic) -magnesium reagent can be prepared by halogen-metal exchange between an aryl halide compound and a commercially available organometallic reagent such as a reagent of alkyl lithium, such as n-, sec- or tert-butyl lithium, or a Grignard reagent such as isopropylmagnesium bromide, or metallic magnesium, for example.
The solvent used in this step varies according to the starting material and the reagent used, and is not particularly limited as long as it does not inhibit the reaction, allow the starting material to dissolve therein to some degree, and always be inert during reaction. Preferable examples of the solvent include organic solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene and toluene, and mixed solvents thereof. The reaction time is not particularly limited, and is usually 0.1 to 48 hours, and preferably 0.1 to 12 hours. The reaction temperature varies according to the starting material, the reagent used and the like, and is preferably maintained to be low, for example, at -78 ° C to minimize the formation of a byproduct.
Favorable results, such as improved yield and reduced reaction time, can be achieved by adding TMEDA (tetramethylethylenediamine), HMPA (hexamethylphosphoramide) or a Lewis acid such as a complex of diethyl boron ether trifluoride (BF3 · OEt2 ) as an additive, for example.
5-4. Stage 5-4:
This step is a step to obtain a compound (5-5) by subjecting the compound (5-4) to a NO-link reducing cleavage reaction.
The reduction reaction of the bond cleavage can NOT be carried out under conditions using zinc-acetic acid, a metal catalyst such as platinum hydrogen oxide, or lithium aluminum hydride, for example.
The reaction using zinc, such as zinc-acetic acid, can be carried out under the same conditions as described in J. Org. Chem. 2003, 68, 1207-1215 and Org. Lett. 7 (2005) 25, 5741-5742, for example. Examples of the acid used include acetic acid, formic acid and hydrochloric acid. The solvent used in the reaction is not
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particularly limited as long as it does not inhibit the reaction and allows the starting material to dissolve therein to some extent. Examples of the solvent include methanol, ethanol, 1,4-dioxane, THF and water. The above acid can also be used as a solvent. The reaction temperature is usually -20 ° C to the reflux temperature of the solvent, and preferably the cooling temperature with ice to the reflux temperature of the solvent. The reaction time is not particularly limited, and is usually 5 minutes to 48 hours, and preferably 5 minutes to 24 hours.
The reaction using a metal catalyst such as hydrogen-platinum oxide can be carried out under the same conditions as described in Tetrahedron: Asymmetry 5 (1994) 6, 1019-1028 and Tetrahedron, Vol. 53, No. 16, p . 5752-5746, 1997, for example. The compound (5-5) can be obtained by hydrogenating the compound (5-4) using as a catalyst platinum oxide in a solvent such as methanol, for example.
The reaction using lithium aluminum hydride can be carried out under the same conditions as those described in Bull. Chem. Soc. Jpn., 66, 2730-2737 (1993), for example. The compound (5-5) can be obtained by reducing the compound (5-4) using lithium aluminum hydride in a solvent such as ether, for example.
5-5. Stage 5-5:
This stage is a stage to obtain a compound (5-6) from the compound (5-5). The thiourea derivative (5-6) can be obtained from the compound (5-5) by a method known to a person skilled in the art.
When the protecting group is a benzoyl group, the compound (5-6) can be obtained in this step by reacting the compound (5-5) with benzoyl isothiocyanate in a solvent such as dichloromethane or toluene. This reaction can be carried out under the same conditions as described in J. Org. Chem. 1994, 59, 19121917, for example. The solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction and allows the starting material to dissolve therein to some extent. Examples of the solvent include dichloromethane, chloroform, toluene, methanol, ethanol, 1,4-dioxane and THF. The reaction temperature is usually -20 ° C to the reflux temperature of the solvent, and preferably the cooling temperature with ice to the reflux temperature of the solvent. The reaction time is not particularly limited, and is usually 5 minutes to 48 hours, and preferably 5 minutes to 24 hours.
When the protecting group is a 9-fluorenemethyloxycarbonyl group (Fmoc group), the compound (5-6) can be obtained at this stage by reacting the compound (5-5) with fluorenemethyloxycarbonyl isothiocyanate in a solvent such as dichloromethane or toluene. This reaction can be carried out under the same conditions as described in J. Org. Chem. 1998, 63, 196-200, for example. The solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction and allows the starting material to dissolve therein to some extent. Examples of the solvent include dichloromethane, chloroform, toluene, methanol, ethanol, 1,4-dioxane and THF. The reaction temperature is usually -20 ° C to the reflux temperature of the solvent, and preferably the cooling temperature with ice to the reflux temperature of the solvent. The reaction time is not particularly limited, and is usually 5 minutes to 48 hours, and preferably 5 minutes to 24 hours.
5-6. Stage 5-6:
This step is a method of obtaining a compound (5-7) by cycling the compound (5-6).
In this reaction, the compound (5-6) can be cycled under various conditions to obtain the compound (5-7) by selecting a protective group of the compound (5-6).
When the protecting group is an Fmoc group or a benzoyl group, for example, the compound (5-7) can be obtained in this reaction by heating the compound (5-6) in a solvent such as methanol in the presence of an acid such as concentrated hydrochloric acid, for example. The solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction and allows the starting material to dissolve therein to some extent. Examples of the solvent include solvents such as methanol, ethanol, 1-propanol and water, mixed solvents thereof, and acids used as a solvent. The reaction can be carried out by causing an equivalent to a large excess of an appropriate acid to act in the presence or absence of such a solvent. Examples of the acid used include concentrated hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid and mixtures thereof. The reaction time is not particularly limited, and is usually 0.5 to 72 hours, and preferably 0.5 to 24 hours. The reaction temperature is usually the cooling temperature with ice to the reflux temperature of the solvent.
When the protecting group is an Fmoc group or a benzoyl group, the compound (5-7) can be obtained by an alternative method 1 by reacting the compound (5-6) with trifluoromethanesulfonic anhydride in a solvent such as dichloromethane in the presence of a base such as pyridine. This reaction can be carried out under the same conditions as described in Chem Bio Chem. 2005, 6, 186-191, for example. The solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction and allows the starting material to dissolve therein to some extent. Examples of the solvent include solvents such as dichloromethane, 1,2-dichloroethane, THF, 1,2-dimethoxyethane and toluene, and mixed solvents thereof. The reaction can lead to
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carried out using 1 to 20 equivalents of an appropriate base in such solvent. Examples of the base used include pyridine, 2,6-lutidine, sodium carbonate, potassium carbonate and mixtures thereof. The reaction time is not particularly limited, and is usually 0.5 to 24 hours, and preferably 0.5 to 12 hours. The reaction temperature is usually -78 ° C to room temperature. When the protecting group is a benzoyl group, the compound (5-7) can be obtained by an alternative method 2 by reacting the compound (5-6) with triphenylphosphine and carbon tetrabromide (or bromine) in a solvent such as dichloromethane. The reaction conditions are the same as those of bromination of a primary alcohol, which are known to a person skilled in the art.
5-7. Stage 5-7:
This step is a method of obtaining the compound (1-7) by deprotecting the protecting group of the compound (5-7). The compound (1-7) can be obtained under deprotection conditions known to a person skilled in the art.
When the protecting group is an Fmoc group, for example, the compound (1-7) can be obtained under the same conditions as those generally used in deprotection of a protective group of an amine compound (such as the conditions described in a document such as TW Green and P. G M. Wuts, "Protective Groups in Organic Chemistry, Third Edition," John Wiley & Sons, p. 506-507 and J. Org. Chem. 1998, 63, 196-200). In this reaction, the compound (1-7) can be obtained by reacting the compound (5-7) with an excess of an amine such as pyrrolidine in a solvent such as acetonitrile, for example. The solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction and allows the starting material to dissolve therein to some extent. Examples of the solvent include dichloromethane, THF and acetonitrile. The reaction can be carried out by having an equivalent to a large excess of an appropriate base act in the presence of such a solvent. Examples of the base used include piperidine, morpholine, pyrrolidine, TBAF and DBU. The reaction time is not particularly limited, and is usually 0.5 to 72 hours, and preferably 0.5 to 24 hours. The reaction temperature is usually the cooling temperature with ice at the reflux temperature of the solvent.
Favorable results, such as improved yield and reduced reaction time, can be achieved by adding a thiol compound such as 1-octanotiol as an additive, for example.
When the protecting group is a benzoyl group, the compound (1-7) can be obtained in this reaction by heating the compound (5-7) in a solvent such as methanol in the presence of a base such as DBU, for example. This reaction can be carried out under the same conditions as described in Synth. Commun. 32 (2), 265-272 (2002), for example. The solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction and allows the starting material to dissolve therein to some extent. Examples of the solvent include solvents such as methanol, ethanol and 1-propanol. The reaction can be carried out using 1 to 20 equivalents of an appropriate base in such solvent. Examples of the base used include DBU. The reaction time is not particularly limited, and is usually 0.5 to 24 hours, and preferably 0.5 to 12 hours. The reaction temperature is usually room temperature to the reflux temperature of the solvent.
The compound of the formula (1-7), wherein at least one hydrogen atom of the amino group is a C1-6 alkyl group which may have 1 to 3 substituents selected from the Substituent Group , a C1-6 alkyl group -carbonyl which may have 1 to 3 substituents selected from the Substituent Group , an aryl C6-14-carbonyl group which may have 1 to 3 substituents selected from the Substituent Group , a C 1-6 alkyl-sulfonyl group which may have 1 to 3 substituents selected from the Substituent Group , an aryl C6-14-sulfonyl group which may have 1 to 3 substituents selected from the Substituent Group , a hydrocarbon ring group of C3-8 which may have 1 to 3 substituents selected from the Substituent Group , or a 5-10 membered heterocyclic group that may have 1 to 3 substituents selected from Substituent Group , can be obtained by further reacting the compound (1-7) obtained in General Preparation Method 5 with a corresponding or similar halide compound such as a C1-6 alkyl halide.
6. Method 6 of General Preparation:
[Formula 13]
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In the formula, Ring A, R3, R4, R5, R6, Y, Z, L, LV and Ring B are as defined above, Alk represents a C1-6 alkyl group, R8 represents a hydrogen atom or a C1-4 alkyl group, and L1 represents a single bond or a C1-4 alkyl group, with the proviso that R8 and L1 in the compound (6-6) have up to four carbon atoms in total.
The General Preparation Method 6 is a method for preparing the compound (Ib) of the general formula (I) according to the present invention, wherein L is a single bond, a C2-6 alkenylene group or a C26 alkynylene group , and R1 and R2 are hydrogen atoms, from a compound (6-1) as a raw material through multiple stages from Step 6-1 to Step 6-3.
Compound (6-1) can be prepared from a commercially available product by General Preparation Method 1, General Preparation Method 5, or a combination of General Preparation Method 1 and General Preparation Method 11, and also it can be prepared by a method described in the Preparation Examples within the Examples. The compounds (6-3), (6-4), (6-5) and (6-6) can be commercially available products used directly, they can also be prepared from a commercially available product by a method known by a person skilled in the art, and can be further prepared by a method described in the Preparation Examples within the Examples.
6-1. Stage 6-1:
This step is a step to obtain a compound (6-2) di-t-butoxycarbonylating the compound (6-1). This reaction can be carried out under the same conditions as those generally used in the t-butoxycarbonylation of an amide compound, such as the conditions described in TW Green and PGM Wuts, "Protective Groups in Organic Chemistry, Third Edition", John Wiley & Sons, P. 642-643 and J. Org. Chem. 2005, 70, 2445-2454. The compound (6-2) can be obtained by reacting the compound (6-1) with di-tert-butyl dicarbonate using 4-dimethylaminopyridine as a base in a solvent such as THF, for example.
The solvent used in this reaction is not particularly limited as long as it does not inhibit the reaction. Preferable examples of the solvent include organic solvents such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dichloromethane, DMF and acetonitrile, and mixed solvents thereof. Examples of the base used include triethylamine, 4-dimethylaminopyridine, DBU and mixtures thereof. A catalytic amount is used in excess of, and more preferably 0.1 to 5 equivalents of the base with respect to the compound (6-1). Two equivalents to an excess of, and more preferably 2 to 10 equivalents of di-tert-butyl dicarbonate are used with respect to the compound (6-1). The reaction time is not particularly limited, and is usually 5 minutes to 24 hours, and preferably 5 minutes to 12 hours. The reaction temperature is usually -20 ° C to the reflux temperature of the solvent, and more preferably 0 ° C to the reflux temperature of the solvent.
6-2. Stage 6-2:
This step is a step to obtain a compound (6-7) by coupling reaction of the compound (6-2) with the compound (6-3), (6-4), (6-5) or (6-6 ) using a transition metal. This reaction can be carried out in
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the conditions commonly used in coupling reaction using a transition metal (such as Suzuki coupling reaction, Stille coupling reaction, Sonogashira reaction or Heck reaction).
Examples of the Suzuki coupling reaction include reactions in documents such as J. Org. Chem. 2007, 72, 7207-7213, J. Am. Chem. Soc. 2000, 122, 4020-4028 and J. Org. Chem. 2007, 72, 5960-5967. Examples of the Stille coupling reaction include the reaction in a document such as J. Am. Chem. Soc. 1990, 112, 3093-3100. Examples of the Sonogashira reaction include reactions in documents such as
J. Org. Chem. 2007, 72, 8547-8550 and J. Org. Chem. 2008, 73, 234-240. Examples of the Heck reaction include the reaction in a document such as J. Am. Chem. Soc. 2005, 127, 16900-16911. The organometallic catalyst used in this reaction is not particularly limited. Preferable examples of the organometallic catalyst include metal catalysts such as tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), [1,1'-bis (diphenylphosphino) ferrocene dichloride] palladium (II), bis (tert-butylphosphine) ) palladium (0), palladium (II) acetate and [1,3-bis (diphenylphosphino) propane] nickel (II), and mixtures of these metal catalysts. The amount of the organometallic catalyst used is about 0.001 to 0.5 equivalents with respect to the raw material. The amount of the compound (6-3), (6-4), (6-5) or (6-6) used is not particularly limited, and is usually 1 to 5 equivalents with respect to the compound (6-2). The solvent used in this reaction is not particularly limited as long as it does not inhibit the reaction. Preferable examples of the solvent include benzene, toluene, xylene, N, N-dimethylformamide, 1-methyl-2-pyrrolidone, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, acetonitrile and propionitrile. The reaction temperature is not particularly limited, and it is usually the temperature of cooling with ice to the reflux temperature of the solvent, and preferably room temperature to the reflux temperature of the solvent, for example. The reaction time is not particularly limited, and is usually 0.5 to 48 hours, and preferably 0.5 to 24 hours.
A more preferable result, such as improved performance, can be achieved by carrying out this reaction in the presence of a base or salt. Such base or salt is not particularly limited. Preferable examples of the base or salt include bases or salts such as sodium carbonate, potassium carbonate, barium hydroxide, cesium carbonate, potassium phosphate, potassium fluoride and its solutions, and triethylamine, N, N-diisopropylethylamine, lithium chloride and copper iodide (I).
6-3. Stage 6-3:
This stage is a stage to synthesize the compound (Ib) from the compound (6-7) as a raw material using a method described in the previous preparation method (Step 3-4).
The compound of the formula (I) according to the present invention, wherein at least one of R1 and R2 is a C1-6 alkyl group which may have 1 to 3 substituents selected from the Substituent Group , a C1-6 alkyl group -carbonyl which may have 1 to 3 substituents selected from the Substituent Group , an aryl C6-14-carbonyl group which may have 1 to 3 substituents selected from the Substituent Group , a C 1-6 alkyl-sulfonyl group which may have 1 to 3 substituents selected from the Substituent Group , an aryl C6-14-sulfonyl group which may have 1 to 3 substituents selected from the Substituent Group , a hydrocarbon ring group of C3-8 which may have 1 to 3 substituents selected from the Substituent Group , or a 5-10 membered heterocyclic group that may have 1 to 3 substituents selected from Substituent Group , can be obtained by further reacting the compound (Ib) obtained in Method 6 of General Preparation with a corresponding or similar halide compound such as a C1-6 alkyl halide.
7. General Preparation Method 7: image14
In the formula, Ring A, Ring B, R3, R4, R5, R6, Z, Y, L and LV are as defined above.
The General Preparation Method 7 is a method for preparing the compound (Ib) of the general formula (I) according to the present invention, in which L is a single bond and R1 and R2 are hydrogen atoms, from a compound (7-1) as raw material through Stage 7-1 to Stage 7-2.
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The compound (7-1) can be prepared from a commercially available product by General Preparation Method 1, General Preparation Method 5, or a combination of General Preparation Method 1 and General Preparation Method 11, and also it can be prepared by a method described in the Preparation Examples within the Examples.
7-1 Stage 7-1:
This step is a step to obtain a compound (7-2) by benzyloxycarbonylation of the compound (7-1).
The reaction can be carried out under the same conditions as those generally used in benzyloxycarbonylation (modification with group Z) of an amine compound, such as the conditions described in a document such as TW Green and P. G M. Wuts, "Protective Groups in Organic Chemistry, Third Edition," John Wiley & Sons, P. 531-537. The compound (7-2) can be obtained by reacting the compound (7-1) with benzyl chloroformate in a mixed 1,4-dioxane solvent and saturated sodium bicarbonate solution, for example.
7-2 Stage 7-2:
This stage is a step to synthesize the compound (Ib) from the compound (7-2) as a raw material using a method described in the previous preparation method (Step 6-2).
The compound of the formula (I) according to the present invention, wherein at least one of R1 and R2 is a C1-6 alkyl group which may have 1 to 3 substituents selected from the Substituent Group , a C1-6 alkyl group -carbonyl which may have 1 to 3 substituents selected from the Substituent Group , an aryl C6-14-carbonyl group which may have 1 to 3 substituents selected from the Substituent Group , a C 1-6 alkyl-sulfonyl group which may have 1 to 3 substituents selected from the Substituent Group , an aryl C6-14-sulfonyl group which may have 1 to 3 substituents selected from the Substituent Group , a hydrocarbon ring group of C3-8 which may have 1 to 3 substituents selected from the Substituent Group , or a 5-10 membered heterocyclic group that may have 1 to 3 substituents selected from the Substituent Group , can be obtained by further reacting the compound (Ib) obtained in General Preparation Method 7 with a corresponding or similar halide compound such as a C1-6 alkyl halide.
8. Method 8 of General Preparation: image15
In the formula, Ring A, Ring B, R3, R4, R5, R6, Y, Z, L and LV are as defined above.
The General Preparation Method 8 is a method for preparing the compound (Ib) of the general formula (I) according to the present invention, in which L is a single bond and R1 and R2 are hydrogen atoms, from a compound (6-2) as a raw material through multiple stages from Stage 8-1 to Stage 8-3.
The compound (6-2) can be prepared from a commercially available product by the General Preparation Method 6, and can also be prepared by a method described in the Preparation Examples within the Examples. A compound (8-2) can be a commercially available product used as such,
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It can also be prepared from a commercially available product by a method known to a person skilled in the art, and can be further prepared by a method described in the Preparation Examples within the Examples.
8-1. Stage 8-1:
This step is a step to obtain a compound (8-1) by coupling reaction of the compound (6-2) using a transition metal.
The reaction at this stage can be carried out under the same conditions as those commonly used in coupling reaction using a transition metal, such as the conditions described in Org. Lett. 2007, Vol. 9, No. 4, 559-562 and Bioorg. Med. Chem, 14 (2006) 4944-4957. Specifically, the compound (8-1) can be obtained by reacting the compound (6-2) with bis (pinacolato) diborane under heating conditions in a solvent such as DMF in the presence of a catalyst such as potassium acetate or dichloride. [1,1'bis (diphenylphosphino) ferrocene] palladium (II), for example.
The organometallic catalyst used in this reaction is not particularly limited. Preferable examples of the organometallic catalyst include metal catalysts such as dichlorobis (triphenylphosphine) palladium (II), [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride, bis (tert-butylphosphine) palladium (0), palladium (II) acetate and [1,3bis (diphenylphosphino) propane] nickel (II). The amount of the organometallic catalyst used is about 0.001 to 0.5 equivalents with respect to the raw material. The solvent used in this reaction is not particularly limited as long as it does not inhibit the reaction. Preferable examples of the solvent include benzene, toluene, xylene, N, N-dimethylformamide, 1-methyl-2-pyrrolidone, dimethyl sulfoxide, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, acetonitrile and propionitrile. The reaction temperature is not particularly limited, and it is usually the temperature of cooling with ice to the reflux temperature of the solvent, and preferably room temperature to the reflux temperature of the solvent, for example. The reaction time is not particularly limited, and is usually 0.5 to 72 hours, and preferably 0.5 to 24 hours.
A more preferable result, such as improved performance, can be achieved by carrying out this reaction in the presence of a base. Such a base is not particularly limited. Preferable examples of the base include bases such as potassium acetate, sodium acetate, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, potassium fluoride, triethylamine and N, N-diisopropylethylamine.
8-2. Stage 8-2:
This step is a step to synthesize a compound (8-3) from the compound (8-1) as a raw material using a method described in the previous preparation method (Step 6-2).
8-3 Stage 8-3:
This stage is a stage to synthesize the compound (Ib) from the compound (8-3) as a raw material using a method described in the previous preparation method (Step 3-4).
The compound of the formula (I) according to the present invention, wherein at least one of R1 and R2 is a C1-6 alkyl group which may have 1 to 3 substituents selected from the Substituent Group , a C1-6 alkyl group -carbonyl which may have 1 to 3 substituents selected from the Substituent Group , an aryl C6-14-carbonyl group which may have 1 to 3 substituents selected from the Substituent Group , a C 1-6 alkyl-sulfonyl group which may have 1 to 3 substituents selected from the Substituent Group , an aryl C6-14-sulfonyl group which may have 1 to 3 substituents selected from the Substituent Group , a hydrocarbon ring group of C3-8 which may have 1 to 3 substituents selected from the Substituent Group , or a 5-10 membered heterocyclic group that may have 1 to 3 substituents selected from Substituent Group , can be obtained by further reacting the compound (Ib) obtained in Method 8 of General Preparation with a corresponding or similar halide compound such as a C1-6 alkyl halide.
9. General Preparation Method 9:
[Formula 16]
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In the formula, Ring A, Ring B, R3, R4, R5, R6, Y and Z are as defined above.
The General Preparation Method 9 is a method for preparing the compound (Ia) of the general formula (I) according to the present invention, in which L is -NHCO- and R1 and R2 are hydrogen atoms, from a compound (8-1) as a raw material through multiple stages from Stage 9-1 to Stage 9-4.
The compound (8-1) can be prepared from a commercially available product by the General Preparation Method 8, and can also be prepared by a method described in the Preparation Examples within the Examples.
9-1. Stage 9-1:
This step is a step to obtain a compound (9-1) by reacting the compound (8-1) with sodium azide in the presence of a copper catalyst.
The reaction at this stage can be carried out under the same conditions as described in Org. Lett. 2007, Vol. 9, No. 5, 761-764 and Tetrahedron Lett. 2007, 48, 3525-3529, for example. Specifically, the compound (9-1) can be obtained by reacting the compound (8-1) with sodium azide at room temperature using a solvent such as methanol in the presence of a catalyst such as copper (II) acetate, for example .
The catalyst used in this reaction is not particularly limited. Preferable examples of the catalyst include metal catalysts such as copper (II) acetate, copper (II) sulfate, copper (I) iodide and copper (I) chloride. The amount of the catalyst used is not particularly limited, and is usually about 0.1 to 0.5 equivalents with respect to the raw material. The solvent used in this reaction is not particularly limited as long as it does not inhibit the reaction and allows the starting material to dissolve therein to some extent. Preferable examples of the solvent include methanol, N, N-dimethylformamide, 1-methyl-2-pyrrolidone, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, acetonitrile, propionitrile and dichloromethane. The reaction temperature is not particularly limited, and it is usually the temperature of cooling with ice to the reflux temperature of the solvent, and preferably room temperature to the reflux temperature of the solvent, for example. The reaction time is not particularly limited, and is usually 0.5 to 100 hours, and preferably 1 to 72 hours.
A more preferable result, such as improved performance, can be achieved by carrying out this reaction in an oxygen atmosphere.
9-2. Stage 9-2:
This step is a step to obtain a compound (9-2) by azide reduction reaction of the compound (9-1). The reaction at this stage can be carried out under the same conditions as described in
J. Org. Chem. 2003, 68, 4693-4699, for example. Specifically, the compound (9-2) can be obtained by dissolving the compound (9-1) in a solvent such as methanol, and reacting the solution with sodium borohydride, for example.
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9-3 Stage 9-3:
This step is a step to synthesize a compound (9-3) from the compound (9-2) as a raw material using a method described in the previous preparation method (Step 3-3).
9-4. Stage 9-4:
This stage is a stage to synthesize the compound (Ia) from the compound (9-3) as a raw material using a method described in the previous preparation method (Step 3-4).
The compound of the formula (I) according to the present invention, wherein at least one of R1 and R2 is a C1-6 alkyl group which may have 1 to 3 substituents selected from the Substituent Group , a C1-6 alkyl group -carbonyl which may have 1 to 3 substituents selected from the Substituent Group , an aryl C6-14-carbonyl group which may have 1 to 3 substituents selected from the Substituent Group , a C 1-6 alkyl-sulfonyl group which may have 1 to 3 substituents selected from the Substituent Group , an aryl C6-14-sulfonyl group which may have 1 to 3 substituents selected from the Substituent Group , a hydrocarbon ring group of C3-8 which may have 1 to 3 substituents selected from the Substituent Group , or a 5-10 membered heterocyclic group that may have 1 to 3 substituents selected from the Substituent Group , can be obtained by further reacting the compound (Ia) obtained in Method 9 of General Preparation 1 with a corresponding or similar halide compound such as a C1-6 alkyl halide. Alternatively, the compound of the formula (I) according to the present invention, wherein L is -NRLCO- (in which RL is a C1-6 alkyl group which may have 1 to 3 substituents selected from the Substituent Group ) , can be obtained by reacting the compound (Ia) obtained in the General Preparation Method 9 with a corresponding or similar halide compound such as a
20 C1-6 alkyl halide.
The compound of the formula (I) according to the present invention, wherein L is -NRLSO2- (where RL is a hydrogen atom), can be obtained using a sulfonyl compound or corresponding sulfonyl halide compound instead of compound (3-4) or (3-5) used in Method 9 of General Preparation. The compound of the formula (I) according to the present invention, wherein L is -NRLSO2- (in which RL is a C1-6 alkyl group which may have 1 to
25 3 substituents selected from Substituent Group ), can be obtained by further reacting this compound with a corresponding or similar halide compound such as a C1-6 alkyl halide.
10. General Preparation Method 10: image17
[Formula 18]
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In the formula, Ring A, Ring B, R3, R4, R5, R6, L and LV are as defined above; Ring D represents a C6-14 aryl group that may have 1 to 3 substituents selected from the Substituent Group , or a 5 to 6 membered heteroaryl group that may have 1 to 3 substituents selected from the Substituent Group ; R9 represents a C6-14 aryl group that may have 1 to 3 substituents selected from the Substituent Group , a 5-10 membered heterocyclic group that may have 1 to 3 substituents selected from the Substituent Group , a C3-8 cycloalkyl group which may have 1 to 3 substituents selected from the Substituent Group , a C1-6 alkyl group that may have 1 to 3 substituents selected from the Substituent Group , or a carbocyclic group 10 of 3 to 10 members that may have 1 to 3 substituents selected from the Substituent Group ; R10 and
R11
they are each independently a hydrogen atom, an aryl group of C6-14 that can have 1 to 3
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substituents selected from the Substituent Group , a 5-10 membered heterocyclic group that may have 1 to 3 substituents selected from the Substituent Group , a C3-8 cycloalkyl group that may have 1 to 3 substituents selected from the Substituent Group , a group C1-6 alkyl which may have 1 to 3 substituents selected from the Substituent Group , or a carbocyclic group of 3 to 10 members which may have 1 to 3 substituents selected from the Substituent Group ; or R10 and R11, together, can form a C3-8 cycloalkyl group that can be substituted on the carbon atom or atoms with 1 to 2 substituents selected from an oxygen atom, a sulfur atom, a sulfone and -N ( RM) - (in which RM is as defined above); R12 represents a C6-14 aryl group that may have 1 to 3 substituents selected from the Substituent Group , a 5-10 membered heterocyclic group that may have 1 to 3 substituents selected from the Substituent Group , a C3-8 cycloalkyl group which may have 1 to 3 substituents selected from the Substituent Group , a C1-6 alkyl group that may have 1 to 3 substituents selected from the Substituent Group , or a carbocyclic group of 3 to 10 members that may have 1 to 3 substituents selected of the Substituent Group ; R13 represents a C7-12 aralkyl group that may have 1 to 3 substituents selected from the Substituent Group ; and Prt2 represents an amine protecting group such as a 2,4-dimethoxybenzyl group or a benzyloxycarbonyl group.
The General Preparation Method 10 is a method for preparing the compounds (Im) to (Iq) of the general formula
(I) according to the present invention, in which Z is -NRM- (in which RM is a hydrogen atom, a C1-6 alkyl group which may have 1 to 3 substituents selected from the Substituent Group , a cycloalkyl group of C3-8 which may have 1 to 3 substituents selected from the Substituent Group , a C 1-6 alkylcarbonyl group which may have 1 to 3 substituents selected from the Substituent Group , a C6-14 arylcarbonyl group which may have 1 to 3 substituents selected from the Substituent Group , a C1-6 alkylsulfonyl group that may have 1 to 3 substituents selected from the Substituent Group , an arylsulfonyl group of C6-14 that may have 1 to 3 substituents selected from the Substituent Group , an aryl group of C6-14 which may have 1 to 3 substituents selected from the Substituent Group , or a 5-10 membered heterocyclic group that may have 1 to 3 substituents selected from the Substituent Group ) and R1 and R2 are atoms of hydrogen, from a compound (10-1) as raw material through various stages from Stage 10-1 to Stage 10-6.
The compound (10-1) may be prepared from a commercially available product by General Preparation Method 5, General Preparation Method 6, General Preparation Method 8, General Preparation Method 9, or a combination of these methods, and can also be prepared by a method described in the Preparation Examples within the Examples.
10-1 Stage 10-1:
This step is a step to obtain a compound (10-2) by deprotecting the amino group of the compound (10-1).
The reaction can be carried out under the same conditions as those generally used in the deprotection of a protective group of an amine compound, such as the conditions described in a document such as T.
W. Green and P. G M. Wuts, “Protective Groups in Organic Chemistry, Third Edition,” John Wiley & Sons, P. 494
572.
The amino protecting group used in this stage is not particularly limited. When Prt2 is a 2,4-dimethoxybenzyl group, for example, the compound (10-2) can be obtained at this stage under the same conditions as generally used (such as the conditions described in a document such as Tetrahedron Vol. 47, no. 26, p. 4591-4602, 1991). In this step, when Prt2 is a 2,4-dimethoxybenzyl group, a Boc group can be deprotected simultaneously with deprotection of the 2,4-dimethoxybenzyl group. When Prt2 is a 2,4-dimethoxybenzyl group at this stage, the solvent used in this stage is not particularly limited as long as it does not inhibit the reaction and allows the starting material to dissolve therein to some extent. For example, the first stage reaction solvent may be methylene chloride or chloroform, and the second stage reaction solvent may be methanol. The reaction temperature at this stage is usually 0 ° C to room temperature. The reaction time at this stage is not particularly limited, and is usually 0.5 to 24 hours, and preferably 0.5 to 12 hours. When Prt2 is a benzyloxycarbonyl group, compound (10-2) can be obtained by deprotecting compound (10-1) by hydrogenation using palladium-carbon as a catalyst in a solvent such as an alcohol, for example.
10-2 Stage 10-2:
This step is a step to synthesize the compound (Im) from the compound (10-2) as a raw material using a method described in the previous preparation method ((Step 3-3) and (Step 3-4)).
10-3 Stage 10-3:
This step is a step to synthesize the compound (In) from the compound (10-2) as a raw material using a method described in Step 3-4 after the reductive amination reaction with a reducing agent such as borane or a composed of a boron hydride complex, for example. Examples of the reductive amination reaction using a compound of a boron hydride complex include a method described in a document.
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just like J. Org. Chem. 1996, 61, 3849. Examples of the compound of a boron hydride complex that can be used include sodium borohydride, sodium cyanoborohydride and sodium triacetoxyborohydride.
10-4 Stage 10-4:
This step is a step to synthesize the compound (Io) from the compound (10-2) as a raw material using a method described in Step 3-4 after sulfonylating the amino group using a sulfonyl chloride derivative known to a person expert in the art.
10-5 Stage 10-5:
This step is a step to synthesize the compound (Ip) from the compound (10-2) as a raw material using a method described in Step 3-4 after the coupling reaction with a compound (15-1) or (15 -2). In the first stage of this stage a reaction such as coupling using a transition metal complex or the like is used,
or nucleophilic aromatic substitution (SNAr reaction).
The reaction in the first stage of this stage can be carried out under the same conditions as described in Org. Lett. 2007, Vol. 9, No. 5, 761-764 and Org. Lett. 2003, Vol., 5, No. 23, 4397-4400, for example. Specifically, the compound (10-2) can be reacted with the compound (15-1) at room temperature up to 50 ° C using a solvent such as dichloromethane in the presence of a 4A molecular sieve and a catalyst such as copper (II) acetate , for example.
The catalyst used in this reaction is not particularly limited. Preferable examples of the catalyst include metal catalysts such as copper (II) acetate, copper (II) sulfate, copper (I) iodide, and copper (I) chloride. The amount of the catalyst used is not particularly limited, and is usually about 0.1 to 0.5 equivalents with respect to the raw material. The solvent used in this reaction is not particularly limited as long as it does not inhibit the reaction and allows the starting material to dissolve therein to some extent. Preferable examples of the solvent include N, N-dimethylformamide, 1-methyl-2-pyrrolidone, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, acetonitrile, propionitrile and dichloromethane. The reaction temperature is not particularly limited, and it is usually the temperature of cooling with ice to the reflux temperature of the solvent, and preferably room temperature to the reflux temperature of the solvent, for example. The reaction time is not particularly limited, and is usually 0.5 to 100 hours, and preferably 1 to 72 hours.
A more preferable result, such as improved performance, can be achieved by carrying out this reaction in an oxygen atmosphere.
When the first stage in this stage is a coupling using a transition metal complex or the like as a catalyst, the reaction can be carried out using the compound (10-2) and the compound (15-2), which is a derivative of aryl halide, a derivative of heteroaryl halide, a derivative of aryloxytri fluoromethanesulfonate or a derivative of heteroaryloxy trifluoromethanesulfonate, under the same conditions as commonly used (such as the conditions described in a document such as Org. Lett. 2002, Vol 4, No. 4, 581). The aryl halide derivative, the heteroaryl halide derivative, the aryloxy trifluoromethanesulfonate derivative or the heteroaryloxy trifluoromethanesulfonate derivative used in this step can be a commercially available product used as such, and can also be prepared from a commercial product available by a method known to a person skilled in the art. Examples of the transition metal complex used in this step include dichlorobis (triphenylphosphine) palladium (II), tetrakis (triphenylphosphine) palladium (0), tris (dibenzylidenacetone) palladium (0) and a copper complex with diolean ligand. In this reaction, a phosphorus ligand (such as preferably triphenylphosphine, tri-o-tolylphosphine, tri-tert-butylphosphine, 2,2'bis (diphenylphosphino) -1,1'-binaphthyl or 1,1 'can be additionally added -bis (diphenylphosphino) ferrocene) in order to obtain favorable results (such as reduced reaction temperature, reduced reaction time and improved yield). When the transition metal complex used is a palladium complex, the reaction at this stage is preferably carried out in a nitrogen or argon atmosphere. The solvent used in this stage is not particularly limited as long as it does not inhibit the reaction and allows the starting material to dissolve therein to some extent. For example, when the transition metal complex used is a palladium complex, N, N-dimethylformamide, N-methyl-2-pyrrolidone, 1,4-dioxane, toluene, xylene or the like can be used. When the transition metal complex used is a copper complex with diol, 2-propanol or the like can be used. The reaction temperature at this stage is usually the ambient temperature to the reflux temperature of the solvent. The reaction time at this stage is not particularly limited, and is usually 0.5 to 72 hours, and preferably 0.5 to 24 hours.
When the first stage in this stage is a nucleophilic aromatic substitution (SNAr reaction), the reaction can be carried out using the compound (10-2) and the compound (15-2) which is an aryl halide derivative, a heteroaryl halide derivative, an aryloxy trifluoromethanesulfonate derivative or a heteroaryloxy trifluoromethanesulfonate derivative in the presence of a base under the same conditions as commonly used. The aryl halide derivative, the heteroaryl halide derivative, the aryloxy trifluoromethanesulfonate derivative or the heteroaryloxy trifluoromethanesulfonate derivative used in this step can be a commercially available product used as such, and can also be prepared from a commercial product available through
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a method known to a person skilled in the art. The nucleophilic aromatic substitution (SNAr reaction) used at this stage can be carried out under the same conditions as generally used (such as the conditions according to the methods described in documents such as Org. Prep. Proced. Int. 39 (2007) 4, 399402, Bioorg. Med. Chem. Lett. 15 (2005) 9, 2409-2413 and Bioorg. Med. Chem. Lett. 15 (2005) 3, 719-723). The solvent used in this stage is not particularly limited as long as it does not inhibit the reaction and allows the starting material to dissolve therein to some extent. Examples of the solvent that can be used include N, N-dimethylformamide, N-methyl-2-pyrrolidone, dimethylsulfoxide and acetonitrile. The base used in this stage is not particularly limited. Examples of the base include potassium carbonate, sodium carbonate, sodium hydride and tetrabutylammonium fluoride. Potassium carbonate, sodium carbonate and tetrabutylammonium fluoride are preferably used. The reaction temperature at this stage is usually the ambient temperature to the reflux temperature of the solvent. The reaction time at this stage is not particularly limited, and is usually 0.5 to 24 hours, and preferably 0.5 to 12 hours.
10-6. Stage 10-6:
This step is a step to synthesize the compound (Iq) from the compound (10-2) as a raw material using a method described in Step 3-4 after the N-alkylation reaction of the amine compound.
The first stage in this reaction can be carried out under the same conditions as those commonly used in the N-alkylation reaction of an amine compound (such as the conditions described in J. Med. Chem. 2002, 45, 3794-3804 and J. Med. Chem. 2000, 43, 3809-3812).
The compound of the formula (I) according to the present invention, wherein at least one of R1 and R2 is a C1-6 alkyl group which may have 1 to 3 substituents selected from the Substituent Group , a C1-6 alkyl group -carbonyl which may have 1 to 3 substituents selected from the Substituent Group , an aryl C6-14-carbonyl group which may have 1 to 3 substituents selected from the Substituent Group , a C 1-6 alkyl-sulfonyl group which may have 1 to 3 substituents selected from the Substituent Group , an aryl C6-14-sulfonyl group which may have 1 to 3 substituents selected from the Substituent Group , a hydrocarbon ring group of C3-8 which may have 1 to 3 substituents selected from the Substituent Group , or a 5-10 membered heterocyclic group that may have 1 to 3 substituents selected from the Substituent Group , can be obtained by further reacting the compounds (Im) to (Iq) thus obtained from the general formula (I), and n where R1 and R2 are hydrogen atoms, with a corresponding or similar halide compound, such as a C1-6 alkyl halide.
11. General Preparation Method 11: image19
In the formula, Ring A, R3, R4, R5, R6, R7, Y and Z are as defined above.
The General Preparation Method 11 is a method for preparing a compound (1-4) which is a synthetic intermediate of the compound (I) according to the present invention from a compound (1-3) as a raw material through Step 11-1 to Stage 11-2.
The compound (1-3) can be prepared from a commercially available product by General Preparation Method 1, and can also be prepared by a method described in the Preparation Examples within the Examples.
11-1 Stage 11-1:
This stage is a stage to obtain a compound (11-1) by alkaline hydrolysis of the compound (1-3).
The reaction can be carried out under the same reaction conditions as described in J. Med. Chem., 33 (9), 2621-2629 (1990), for example.
Specifically, the compound (11-1) can be obtained by adding a base such as sodium hydroxide to a solution of the compound (1-3), stirring the mixture for several hours to a day, and then treating the solution with an acid, such as a citric acid solution, for example.
The solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction and allows the starting material to dissolve therein to some extent. Examples of the solvent include methanol, ethanol, 2
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Propanol, tetrahydrofuran and 1,4-dioxane. The base used is not particularly limited, and is preferably sodium hydroxide, potassium hydroxide or lithium hydroxide, for example. The amount of the base used is equivalent to a large excess, and preferably 1 to 20 equivalents with respect to the compound (1-3). The reaction time is not particularly limited, and is usually 1 to 24 hours, and preferably 1 to 6 hours. The
The reaction temperature is not particularly limited, and it is usually room temperature to the reflux temperature of the solvent.
11-2 Stage 11-2:
This step is a step to obtain the compound (1-4) by subjecting the compound (11-1) to a reduction reaction.
Compound (1-4) can be obtained by converting compound (11-1) into a mixed acid anhydride, and making
10 then react the mixed acid anhydride with sodium borohydride. The mixed acid anhydride can be synthesized by a method known to a person skilled in the art. The synthesis is carried out by reacting the compound (11-1) with a chloroformate, such as ethyl chloroformate in the presence of a base such as triethylamine, for example. One to two equivalents of the chloroformate and the base are used with respect to the compound (11-1). The reaction temperature is -30 ° C to room temperature, and preferably -20 ° C
15 to room temperature.
The step of the reaction of the mixed acid anhydride with a reducing agent such as sodium borohydride is carried out by reaction in a solvent such as tetrahydrofuran or 1,2-dimethoxyethane or in a mixed solution of the solvent and water, for example . An equivalent to a large excess of the reducing agent is used, such as sodium borohydride with respect to mixed acid anhydride.
The reaction time is not particularly limited, and is usually 0.5 to 48 hours, and preferably 0.5 to 24 hours. The reaction temperature is not particularly limited, and is usually -78 ° C to the reflux temperature of the solvent, and preferably -20 ° C to room temperature. The solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction and allows the starting material to dissolve therein to some extent. Preferable examples of the solvent include tetrahydrofuran and ether.
25 12. General Preparation Method 12: image20
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In the formula, Prt3 represents a primary hydroxyl protecting group, R14 represents a C1-6 alkyl group, or two R14 together can form a ring, R15 represents a C1-6 alkyl group, and Y, R3, R4, R5 , R6 and LV are as defined above.
The General Preparation Method 12 is a method for preparing a compound (12-4) which is a synthetic intermediate of the compound (I) according to the present invention from the compounds (12-1), (12-5), ( 12-7) and (12-9) as raw materials through various stages from Stage 12-1 to Stage 12-8.
Compounds (12-1), (12-2), (12-5), (12-7), (12-9) and (12-10) can be commercially available products used directly, can also be prepared to starting from a commercially available product by a method known to a person skilled in the art, and can be further prepared by a method described in the Preparation Examples within the Examples.
12-1 Stage 12-1:
This step is a step to obtain a compound (12-3) by reacting the compound (12-1) with the compound (12-2).
This reaction can be carried out under the same conditions as those commonly used for the Oalkylation reaction of an alcoholic compound (such as the conditions described in Tetrahedron Lett. 46 (2005) 45, 7751-7755). In this reaction, the compound (12-3) can be obtained by adding a base, such as sodium hydride to a solution of the compound (12-1) in THF to prepare an alkoxide, and then reacting the alkoxide with the compound ( 12-2), for example. The solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction and allows the starting material to dissolve therein to some extent. Examples of the solvent include solvents such as THF, DMF and dimethylsulfoxide. The reaction can be carried out by having 1 to 3 equivalents of an appropriate base act in the presence of such solvent. Examples of the base used include sodium hydride, potassium hydride and t-butoxypotasium. The reaction time is not particularly limited, and is usually 0.5 to 72 hours, and preferably 0.5 to 12 hours. The reaction temperature is usually -20 ° C to 100 ° C,
A more preferable result, such as improved yield, can be achieved by adding in this reaction a salt such as tetrabutylammonium iodide.
12-2 Stage 12-2:
This stage is a step to obtain aldehyde compound (12-4) by subjecting the alcoholic compound (12-3) to oxidation reaction. The aldehyde compound can be obtained from the alcoholic compound by a method known to a person skilled in the art.
Examples of the known oxidation method used in the reaction include Swern oxidation, Corey-Kim oxidation, Moffatt oxidation, PCC oxidation, PDC oxidation, Dess-Martin oxidation, SO3-pyridine oxidation and TEMPO oxidation.
The solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction and allows the starting material to dissolve therein to some extent. Examples of the solvent include dimethylsulfoxide, tetrahydrofuran, toluene, dichloromethane and chloroform.
The reaction temperature is not particularly limited, and is usually -78 ° C to the reflux temperature of the solvent, and preferably -78 ° C to room temperature. The reaction time is not particularly limited, and is usually 0.5 to 48 hours, and preferably 0.5 to 24 hours.
12-3 Stage 12-3:
This step is a step to synthesize a compound (12-6) from the compound (12-5) as a raw material using a method described in the previous preparation method (Step 12-1).
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12-4. Stage 12-4:
This step is a step to obtain the compound (12-3) by deprotecting the hydroxyl protecting group of the compound (12-6). The hydroxyl protecting group used in this stage is not particularly limited.
This reaction can be carried out under the same conditions as those generally used in deprotection of an alcohol protecting group, such as the conditions described in a document such as TW Green and P. G M. Wuts, "Protective Groups in Organic Chemistry , Third Edition ”, John Wiley & Sons, P 17-245.
12-5. Stage 12-5:
This step is a step to synthesize a compound (12-8) from the compound (12-7) as a raw material using a method described in the previous preparation method (Step 12-1).
12-6. Stage 12-6:
This stage is a step to obtain the compound (12-4) by deprotecting the acetal group of the compound (12-8).
This reaction can be carried out under the same conditions as those generally used in deprotection of an aldehyde group, such as the conditions described in a document such as TW Green and P. G M. Wuts, "Protective Groups in Organic Chemistry, Third Edition ”, John Wiley & Sons, P. 293-329
12-7. Stage 12-7:
This step is a step to obtain a compound (12-11) by reacting the compound (12-9) with the compound (12-10).
This reaction can be carried out under the same conditions as those commonly used in the O-alkylation reaction of an alcoholic compound (such as the conditions described in J. Chem. Soc., Perkin Trans, 1, 1999, 3143-3155 ). In this reaction, the compound (12-11) can be obtained by adding a base such as sodium hydride to a solution of the compound (12-9) in THF to prepare an alkoxide, and then reacting the alkoxide with the compound (12 -10), for example. The solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction and allows the starting material to dissolve therein to some extent. Examples of the solvent include solvents such as THF, DMF and dimethylsulfoxide. The reaction can be carried out by having 1 to 3 equivalents of an appropriate base act in the presence of such solvent. Examples of the base used include sodium hydride, potassium hydride and t-butoxypotasium. The reaction time is not particularly limited, and is usually 0.5 to 72 hours, and preferably 0.5 to 12 hours. The reaction temperature is usually -20 ° C to 100 ° C.
A more preferable result, such as improved yield, can be achieved by adding in this reaction a salt such as tetrabutylammonium iodide.
12-8. Stage 12-8:
This stage is a stage to synthesize the compound (12-3) from the compound (12-11) as a raw material using a method described in the previous preparation method ((Stage 1-3) or (Stages 11-1 and 2)).
13. General Preparation Method 13: image22
In the formula, R14 represents a C1-6 alkyl group, or two R14, together, form a ring such as 1,3-dioxolane or 1,3-dioxane, Prt2 represents a protective group such as a 2,4- group dimethoxybenzyl, and R3, R4, R5, R6, Y and LV are as defined above.
The General Preparation Method 13 is a method for preparing a compound (13-5) which is a synthetic intermediate of the compound (I) according to the present invention from a compound (13-1) as a raw material throughout the Step 13-1 to Stage 13-3.
Compounds (13-1) and (13-3) can be commercially available products used directly, they can also be prepared from a commercially available product by a method known to a person
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skilled in the art, and can be further prepared by a method described in the Preparation Examples within the Examples.
13-1 Stage 13-1:
This step is a step to obtain a compound (13-2) protecting the amino group of the compound (13-1).
This reaction can be carried out under the same conditions as those generally used in the protection of an amino group, such as the conditions described in a document such as TW Green and P. G M. Wuts, "Protective Groups in Organic Chemistry, Third Edition ”, John Wiley & Sons, P. 494-572 and J. Med. Chem. 2007, 50, 5493-5508.
13-2 Stage 13-2:
This step is a step to obtain a compound (13-4) by reacting N-alkylation of the compound (13-2) with the compound (13-3).
This reaction can be carried out under the same conditions as those commonly used in the N-alkylation reaction of a compound (13-2) (such as the conditions described in J. Med. Chem. 2007, 50, 5493-5508 ). In this reaction, the compound (13-4) can be obtained by adding a base such as powdered sodium hydroxide, to a solution of the compound (13-2) in toluene, and then reacting the mixture with the compound (13-3 ), for example. The solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction and allows the starting material to dissolve therein to some extent. Examples of the solvent include solvents such as toluene, THF, DMF and dimethylsulfoxide. The reaction can be carried out by having 1 to 5 equivalents of an appropriate base act in such a solvent. Examples of the base used include sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride and t-butoxypotasium. The reaction time is not particularly limited, and is usually 0.5 to 72 hours, and preferably 0.5 to 24 hours. The reaction temperature is usually -20 ° C to 100 ° C.
A more preferable result, such as improved yield, can be achieved by adding in this reaction a salt such as tetrabutylammonium iodide.
13-3 Stage 13-3:
This stage is a step to obtain the compound (13-5) by deprotecting the acetal group of the compound (13-4).
This reaction can be carried out under the same conditions as those generally used in the deprotection of an aldehyde group, such as the conditions described in a document such as TW Green and PGM Wuts, "Protective Groups in Organic Chemistry, Third Edition", John Wiley & Sons, P. 293-329.
When necessary, the compound of the formula (I) according to the present invention obtained in this way can be converted into a pharmaceutically acceptable salt by a conventional method. The salt can be prepared by a method in which methods typically used in the field of organic synthetic chemistry, and the like are appropriately combined. Specific examples of the method include neutralization titration of a free solution of the compound of the present invention with an acid solution. When necessary, the compound of the formula (I) according to the present invention can be converted into a solvate by subjecting the compound to a solvate formation reaction known per se.
The condensed aminodihydrotiazine derivative or pharmaceutically acceptable salt thereof or solvate thereof according to the present invention has an inhibitory effect of A production or an extremely excellent BACE1 inhibitory effect, and is extremely useful as a therapeutic agent for a neurodegenerative disease caused. by A and typified by Alzheimer's type dementia.
The pharmaceutically acceptable salt condensed aminodihydrotiazine derivative thereof or solvate thereof according to the present invention can be formulated by a conventional method. Preferable examples of the dosage form include tablets, coated tablets such as film tablets and sugar-coated tablets, fine granules, granules, powders, capsules, syrups, troches, inhalants, suppositories, injections, ointments, eye drops, nasal drops, ear drops, poultices and lotions.
These solid preparations, such as tablets, capsules, granules and powders, may generally contain 0.01 to 100% by weight, and preferably 0.1 to 100% by weight of the condensed aminodihydrotiazine derivative or its pharmaceutically acceptable salt or solvate thereof. according to the present invention as an active ingredient.
The active ingredient is formulated by mixing ingredients generally used as materials for a pharmaceutical preparation and adding an excipient, a disintegrating agent, a binder, a lubricant, a colorant and a corrector typically used, and adding a stabilizer, an emulsifier, an absorbent, a surfactant, a pH adjuster, a preservative and an antioxidant when necessary, for example, using a conventional method. Examples of such ingredients include animal and vegetable oils such as
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soya bean, beef tallow and synthetic glyceride; hydrocarbons such as liquid paraffin, squalane and solid paraffin; ester oils such as octyldodecyl myristate and isopropyl myristate; higher alcohols such as ketostearyl alcohol and behenyl alcohol; a silicone resin; silicone oil; surfactants such as polyoxyethylene fatty acid ester, sorbitan fatty acid ester, glycerol fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, and a polyoxyethylene polyoxypropylene block copolymer; water soluble polymers such as hydroxyethyl cellulose, acrylic polyacid, a carboxyvinyl polymer; polyethylene glycol, polyvinylpyrrolidone and methylcellulose; lower alcohols such as ethanol and isopropanol; polyhydric alcohols such as glycerol, propylene glycol, dipropylene glycol and sorbitol; sugars such as glucose and sucrose; inorganic powders such as silicic anhydride, magnesium aluminum silicate and aluminum silicate; and pure water. Examples of the excipient used include lactose, corn starch, sucrose, glucose, mannitol, sorbitol, crystalline cellulose and silicon dioxide. Examples of the binder used include vinyl polyalcohol, polyvinyl ether, methylcellulose, ethylcellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, a block copolymer of polypropylene glycol and polyoxyethylene. Examples of the disintegrating agent used include starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin and calcium carboxymethylcellulose. Examples of the lubricant used include magnesium stearate, talc, polyethylene glycol, silica, and hydrogenated vegetable oil. Examples of the dye used include those that are allowed to be added to pharmaceutical substances. Examples of the concealer used include cocoa powder, menthol, empasm, peppermint oil, borneol and cinnamon powder. Obviously, the ingredients are not limited to the above additive ingredients.
For example, an oral preparation is prepared by adding the condensed aminodihydrotiazine derivative or its pharmaceutically acceptable salt or solvate thereof according to the present invention as an active ingredient, an excipient and, when necessary, a binder, a disintegrating agent, a lubricant, a dye, a concealer, and the like, and then forming the powder mixture, fine granules, granules, tablets, coated tablets, capsules, or the like, by a conventional method. Obviously, when necessary, the tablets or granules can be coated appropriately, for example they can be coated with sugar.
For example, a syrup or preparation for injection is prepared by adding a pH adjuster, a solubilizer, an isotonizing agent, and the like, and, when necessary, a solubilizing agent, a stabilizer, and the like, by a conventional method. The injection may be a previously prepared solution, or it may be the powder itself or a powder containing a suitable additive, which dissolves before use. The injection may usually contain 0.01 to 100% by weight, and preferably 0.1 to 100% by weight of the active ingredient. In addition, a liquid preparation for oral administration, such as a suspension or a syrup, can usually contain 0.01 to 100% by weight, and preferably 0.1 to 100% by weight of the active ingredient.
For example, an external preparation can be prepared by any conventional method without specific limitations. As the base material, any of several materials commonly used for a pharmaceutical substance, an almost drug, a cosmetic, or the like can be used. Examples of the base material include materials such as animal and vegetable oils, mineral oils, ester oils, waxes, higher alcohols, fatty acids, silicone oils, surfactants, phospholipids, alcohols, polyhydric alcohols, water soluble polymers, clay minerals and pure water. When necessary, a pH adjuster, an antioxidant, a chelator, a preservative and a fungicide, a colorant, a flavor, or the like can be added. In addition, when necessary, ingredients such as an ingredient having a differentiation inducing effect, a blood flow enhancer, a bactericide, an antiphlogistic, a cell activator, vitamin, amino acid, a humectant and a keratolytic agent can be kneaded.
The dose of the condensed aminodihydrotiazine derivative or its pharmaceutically acceptable salt or solvate thereof according to the present invention varies according to the degree of symptoms, age, sex, body weight, mode of administration, type of salt and specific type of disease, for example. Typically, the active ingredient is administered orally to an adult at about 30 µg to 10 g, preferably 100 µg to 5 g, and more preferably 100 µg to 1 g per day, or is administered to an adult by injection at about 30 ga 1 g, preferably 100 ga 500 mg, and more preferably 100 ga 300 mg per day, in one or several doses, respectively.
The compound of the present invention can be converted into a chemical probe to capture a target protein in a bioactive low molecular weight compound. Specifically, the compound of the present invention can be converted into an affinity chromatography probe, a photoaffinity probe, or the like, by introducing a marker group, a linker, or the like, into a moiety that differs from the structural moiety essential for expression of activity of the compound by a technique described in J. Mass Spectrum. Soc. Jpn. Vol. 51, No. 5, 2003, p. 492498, or in WO 2007/139149, for example.
Examples of the marker, linker or similar group used for the chemical probe include groups shown in the following group consisting of (1) to (5):
(1) protein marker groups such as photoaffinity marker groups (such as a benzoyl group, a benzophenone group, an azido group, a carbonylazide group, a diaziridine group, an enone group, a diazo group and a nitro group) and groups of chemical affinity (such as a substituted ketone group
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in the carbon atom  with a halogen atom, a carbamoyl group, an ester group, an alkylthio group, Michael acceptors such as , -unsaturated ketones and esters, and an oxirane group),

(2)

cleavable linkers such as -SS-, -O-Si-O-, monosaccharides (such as a glucose group and a galactose group) and disaccharides (such as lactose), and enzymatically cleavable oligopeptide linkers,

(3)

fishing label groups such as biotin and 3- (4,4-difluoro-5,7-dimethyl-4H-3a, 4a-diaza-4-bora-sindacen-3-yl) propionyl,

(4)

detectable markers such as radioactive marker groups such as 125I, 32P, 3H and 14C; fluorescent marker groups such as fluorescein, rhodamine, dansyl, umbelliferone, 7-nitrofurazanyl and 3 (4,4-difluoro-5,7-dimethyl-4H-3a, 4a-diaza-4-bora-s-indacen-3-il ) propionyl; chemiluminescent groups such as luciferin and luminol; and heavy metal ions such as lanthanide metal ions and radio ions, and

(5)

groups attached to solid phase supports such as glass beads, glass beds, microtiter plates, agarose beads, agarose beds, polystyrene beads, polystyrene beds, nylon beads and nylon beds.

When a probe is prepared by introducing a marker group or the like selected from the group consisting of (1) to (5) above in the compound of the present invention according to a method described in the previous documents or the like, the probe can be used as a Chemical probe for the identification of labeled proteins useful for investigating, for example, new pharmaceutical targets.
The present invention will be described more specifically below with reference to the Examples, Preparation Examples, and Test Example. However, the present invention is not limited thereto. Abbreviations used in the Examples are conventional abbreviations known to a person skilled in the art. Below are some abbreviations.
THF: Tetrahydrofuran
DMF: N, N-dimethylformamide
TFA: Trifluoroacetic Acid
EDC · HCl: 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride
pTLC: Preparative Thin Layer Chromatography
LC-MS: Liquid Chromatography-Mass Spectrometry
PyBOP: Benzotriazol-1-yloxytris (pyrrolidine) phosphonium hexafluorophosphate
Pd2DBA3: Tris (dibenzylidene ketone) palladium
Pd (t-Bu3P) 2: Bis (tri-t-butylphosphnin) palladium Chemical shifts in proton nuclear magnetic resonance spectra are recorded in units  (ppm) with respect to tetramethylsilane, and coupling constants are recorded in Hertz (Hz) The patterns are designated as s: singlet, d: doublet, t: triplet, q: quartet, br: width.
The preparative columns (2 cm x 25 cm) used for the preparative separation of chiral compounds, CHIRALPAK AD-H, CHIRALPAK IA, CHIRALPAK IB and CHIRALCEL OJ-H, were all manufactured by Daicel Chemical Industries, Ltd.
"Ambient temperature" in the following Examples and Preparation Examples typically refers to about 10 ° C to about 35 ° C. "%" Indicates% by weight unless otherwise specified.
Preparation Example 1
Synthesis of (-) - [(4aR *, 8aS *) - 8a- (5-amino-2-fluorophenyl) -4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-2il] tert-butyl carbamate
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(1) Synthesis of 3-butenyloxyacetaldehyde oxime
Hydroxylamine sulfate (20.5 g), sodium acetate (12.8 g) and water (20 ml) were added to a solution of 3butenyloxyacetaldehyde (17.8 g; J. Chem. Soc., Perkin Trans. 1, 1999, 3143-3155) in ethanol (200 ml). The mixture was stirred at room temperature overnight, and then water was added. The excess ethanol was evaporated under reduced pressure, and the resulting residue was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (6.20 g).
1H-NMR (400 MHz, CDCl3) δ (ppm): 2.36 (m, 2H), 3.53 (dt, J = 6.6, 8.4 Hz, 2H), 4.10 (d, J = 5.6 Hz, 1H), 4.35 (d, J = 4.0 Hz, 1H), 5.10 (m, 2H), 5.82 (m, 1H), 6.91 (t, J = 3.6 Hz, 0.5H), 7.50 (t, J = 5.6 Hz, 0.5H).
(2) Synthesis of 3,3a, 4,5-tetrahydro-7H-pyrano [3,4-c] isoxazole
A solution of 5% sodium hypochlorite (122 ml) was added dropwise to a solution of 3butenyloxyacetaldehyde oxime (5.30 g) in dichloromethane (530 ml) under ice cooling. After stirring at the same temperature for two hours, sodium thiosulfate was added. The aqueous layer was extracted with dichloromethane. The organic layers were combined and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (4.15 g).
1 H-NMR (400 MHz, CDCl3) δ (ppm): 1.79 (ddd, J = 4.4, 12.4, 24.4 Hz, 1H), 2.17 (dd, J = 6.4 , 13.2 Hz, 1H), 3.40 (ddd, J = 6.4, 11.2, 22.0 Hz, 1H), 3.50 (dt, J = 2.0, 12.4 Hz, 1H), 3.80 (dd, J = 8.0, 11.6 Hz, 1H), 4.06 (dd, 4.4, 12.8 Hz, 1H), 4.12 (dd, J = 1 , 2, 13.6 Hz, 1H), 4.63 (dd, J = 8.4, 10.4 Hz, 1H), 4.70 (d, J = 13.6 Hz, 1H).
(3) Synthesis of (±) - (3aR *, 7aS *) - 7a- (2-fluorophenyl) hexahydropyran [3,4-c] isoxazol
2-Bromofluorobenzene (1.85 g) was dissolved in toluene (30 ml), and tetrahydrofuran (10 ml) was added. Butyl lithium (2.73 M; 3.68 ml) was added dropwise at -78 ° C. 2-fluorophenyl lithium was prepared by stirring at the same temperature for one hour. A complex of boron ether trifluoride (1.26 ml) was added to a solution of 3,3a, 4,5-tetrahydro7H-pyran [3,4-c] isoxazole (630 mg) in toluene (70 ml) at -78 ° C. After stirring at the same temperature for 10 minutes, 2-fluorophenyl lithium prepared above was added to the reaction mixture through a cannula. After stirring at the same temperature for one hour, a solution of ammonium chloride was added. The reaction mixture was returned to room temperature, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (1.26 g).
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ESI-MS; m / z 224 [M + + H].
1H-NMR (400 MHz, CDCl3) δ (ppm): 1.83 (m, 2H), 3.09 (m, 1H), 3.64 (m, 1H), 3.68 (ddt, J = 1 , 2, 3.2, 11.6 Hz, 1H), 3.73 (d, J = 6.8 Hz, 1H), 3.78 (d, J = 12.8 Hz, 1H) 4.04 ( m, 1H), 4.10 (dd, J = 1.6, 12.4 Hz, 1H), 6.32 (s, 1H), 7.04 (ddd, J = 1.2, 8.0, 12.4 Hz, 1H), 7.16 (dt, J = 1.6, 7.6 Hz, 1H), 7.28 (m, 1H), 7.93 (dt, J = 1.6, 8 , 4 Hz, 1H).
(4) Synthesis of (±) - [(3S *, 4R *) - 3-amino-3- (2-fluorophenyl) tetrahydropyran-4-yl] methanol
Zinc (11.6 g) was added to a solution of (±) - (3aR *, 7aS *) - 7a- (2-fluorophenyl) hexahydropyran [3,4-c] isoxazole (3.95 g) in acetic acid (78.4 ml), and the mixture was stirred at room temperature overnight. The insoluble matter was removed by filtration through celite, and the solvent was evaporated under reduced pressure. A 0.5 N solution of ice-cold sodium hydroxide was added to the residue. The aqueous layer was extracted with ethyl acetate and a mixed solution of ethyl acetate and tetrahydrofuran. The organic layers were combined and washed with brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (3.45 g).
1H-NMR (400 MHz, CDCl3) δ (ppm): 1.61 (m, 1H), 2.28 (m, 2H), 3.35 (dd, J = 2.8, 11.6 Hz, 2H ), 3.55 (dd, J = 1.6, 11.6 Hz, 1H), 3.63 (m, 1H), 4.16 (m, 2H), 7.06 (ddd, J = 1, 2, 8.0, 12.8 Hz, 1H), 7.20 (dt, J = 1.6, 8.0 Hz, 1H), 7.31 (m, 1H), 7.64 (dt, J = 2.0, 8.0 Hz, 1H).
(5) Synthesis of (±) -9H-fluoren-9-ylmethyl ({[(3S *, 4R *) - 3- (2-fluorophenyl) -4- (hydroxymethyl) tetrahydro-2H-pyran-3yl] amino } carbonothioyl) carbamic
Fluorenylmethyloxycarbonyl isothiocyanate (938 mg) was added to a solution of (±) - [(3S *, 4R *) - 3-amino-3- (2fluorophenyl) tetrahydropyran-4-yl] methanol (683 mg) in dichloromethane (20 ml) The mixture was stirred at room temperature overnight, and then the solvent was evaporated under reduced pressure at room temperature or lower. The residue was purified by silica gel column chromatography to obtain the title compound (1.57 g).
ESI-MS; m / z 529 [M ++ Na].
1H-NMR (400 MHz, CDCl3) δ (ppm): 1.67 (m, 1H), 1.93 (m, 2H), 3.65 (m, 4H), 4.13 (m, 2H), 4.27 (t, J = 6.4 Hz, 1H), 4.55 (m, 2H), 7.02 (dd, J = 4.4, 12.8 Hz, 1H), 7.16 (t , J = 8.0 Hz, 1H), 7.28 (m, 1H), 7.35 (t, J = 7.2 Hz, 2H), 7.44 (t, J = 7.2 Hz, 2H ), 7.58 (d, J = 7.6 Hz, 2H), 7.59 (m, 1H), 7.79 (d, J = 8.0 Hz, 2H), 7.93 (s, 1H ), 10.67 (s, 1 H).
(6) Synthesis of (±) - (4R *, 4aS *) - 8a- (2-fluorophenyl) -4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen -2-ylamine
Concentrated hydrochloric acid (3.00 ml) was added to a solution of (±) -9H-fluoren-9-ylmethyl acid ({[(3S *, 4R *) - 3- (2fluorophenyl) -4- (hydroxymethyl) tetrahydro -2H-piran-3-yl] amino} carbonothioyl) carbamic (8.00 g) in methanol (200 ml), and the mixture was heated at reflux for three hours. The reaction solution was cooled to room temperature, and the solvent was evaporated under reduced pressure. Acetonitrile (200 ml) was added to the residue, and piperidine (40 ml) was added dropwise in a water bath. The mixture was stirred at room temperature for two hours, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain a crude product. The resulting crude product was further purified by silica gel column chromatography to obtain the title compound (3.96 g).
ESI-MS; m / z 267 [M + + H].
1H-NMR (400 MHz, CDCl3) δ (ppm): 1.43 (d, J = 17.0 Hz, 1H), 2.12 (m, 1H), 2.61 (d, J = 15.0 Hz, 1H), 2.91 (m, 1H), 2.96 (dd, J = 4.5, 15.5 Hz, 1H), 3.68 (t, J = 15.5 Hz, 1H), 3.76 (d, J = 14.0 Hz, 1H), 4.09 (m, 2H), 4.58 (sa, 2H), 7.03 (dd, J = 10.0, 16.0 Hz , 1H), 7.12 (t, J = 10.0 Hz, 1H), 7.25 (m, 1H), 7.36 (dt, J = 2.5, 10.0 Hz, 1H).
(7) Synthesis of (±) - [(4R *, 4aS *) - 8a- (2-fluoro-5-nitrophenyl) -4,4a, 5,6,8,8a-hexahydro-7-oxa-3- tia-1-azanaphthalen-2-yl] tert-butyl carbamate
(±) - (4R *, 4aS *) - 8a- (2-fluorophenyl) -4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-2- ilamine obtained in Example 1- (6) of preparation (3.96 g) in concentrated sulfuric acid (20 ml), and smoking nitric acid (specific gravity: 1.53; 731 µl) was added dropwise in a ice bath After stirring at the same temperature for two hours, the reaction mixture was carefully poured into ice. The aqueous layer was neutralized with a solution of sodium bicarbonate and a solution of sodium hydroxide, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain a residue. Tetrahydrofuran (200 ml) was added to the residue, and then triethylamine (10.3 ml) and di-tert-butyl dicarbonate (4.85 g) were added sequentially, followed by stirring at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (5.30 g).
ESI-MS; m / z 41.2 [M ++ H].
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1H-NMR (400 MHz, CDCl3) δ (ppm): 1.53 (s, 9H), 1.55 (m, 1H), 2.21 (m, 1H), 2.62 (dd, J = 3 , 2, 12.8 Hz, 1H), 2.85 (dd, J = 2.8, 13.2 Hz, 1H), 3.00 (m, 1H), 3.67 (dt, J = 2, 4, 12.0 Hz, 1H), 3.74 (d, J = 11.2 Hz, 1H), 3.97 (dd, J = 2.4, 11.6 Hz, 1H), 4.12 ( m, 1H), 7.25 (m, 1H), 8.22 (m, 2H).

(8)

Synthesis of (±) - [(4R *, 4aS *) - 8a- (5-amino-2-fluorophenyl) -4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-2il] tert-butyl carbamate

A saturated solution of ammonium chloride (13.2 ml) was added to a solution of (±) - [(4R *, 4aS *) - 8a- (2-fluoro-5nitrophenyl) -4.4a, 5.6, Tert-butyl 8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-2-yl] carbamate obtained in Example 1

(7)

of preparation (5.30 g) in ethanol (132 ml). Iron powder (5.76 g) was added to the reaction mixture, followed by heating under reflux for 30 minutes. The reaction mixture was cooled to room temperature, and insoluble matter was filtered through celite. The filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (4.56 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1.53 (s, 9H), 1.53 (m, 1H), 2.23 (m, 1H), 2.54 (dd, J = 2 , 4, 12.4 Hz, 1H), 2.98 (dd, J = 4.0, 12.4 Hz, 1H), 3.03 (m, 1H), 3.66 (m, 2H), 4 , 07 (dd, J = 1.6, 12.4 Hz, 1H), 4.12 (m, 1H), 6.57 (m, 2H), 6.86 (dd, J = 8.8, 12 , 4 Hz, 1H).

(9)

Synthesis of (-) - [(4R *, 4aS *) - 8a- (5-amino-2-fluorophenyl) -4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-2il] tert-butyl carbamate

(±) - [(4R *, 4aS *) - 8a- (5-amino-2-fluorophenyl) -4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 was purified -azanaftalen-2yl] tert-butyl carbamate obtained in Example 1- (8) of preparation (100 mg) by CHIRALPAK ™ AD-H (mobile phase: hexane: ethanol = 8.5: 1.5, flow rate: 20 ml / min.), and the fraction was collected with a retention time of 20.9 to 27.8 minutes to obtain the title compound. The same operation was repeated to obtain the title compound (405 mg;> 99% ee) from the crude material (1.00 g).
Preparation Example 2
Synthesis of 5-fluoromethoxypyrazin-2-carboxylic acid
[Formula 27] image24
(1) Synthesis of methyl 5-fluoromethoxypyrazin-2-carboxylate
Fluoromethyl toluene-4-sulphonate (Journal of Labelled Compounds & Radiopharmaceuticals, 46 (6), 555-566; 2003) (344 mg) and cesium carbonate (824 mg) were added to a solution of 5-hydroxypyrazine-2- methyl carboxylate (130 mg) in N, N-dimethylformamide (2.0 ml). The reaction solution was stirred at 70 ° C for five hours and 30 minutes, and then cooled to room temperature. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (18.0 mg).
1H-NMR (400 MHz, CDCl3) δ (ppm): 4.03 (s, 3.H), 6.14 (d, J = 51.2 Hz, 2H), 8.42 (d, J = 1 2 Hz, 1H), 8.94 (d, J = 1.2 Hz, 1H).
(2) Synthesis of 5-fluoromethoxypyrazin-2-carboxylic acid
Potassium trimethylsilanolate (18.6 mg) was added to a solution of methyl 5-fluoromethoxypyrazine-2-carboxylate obtained in Preparation Example 15- (1) (18.0 mg) in tetrahydrofuran (1.0 ml). The reaction solution was stirred at room temperature for one hour. Water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The aqueous layer was made acidic with 1M hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain a crude product of the title compound (10.2 mg). The compound was used for the next reaction without further purification.
1H-NMR (400 MHz, CDCl3) δ (ppm): 6.16 (d, J = 50.8 Hz, 2H), 8.34 (d, J = 1.4 Hz, 1H), 9.05 ( d, J = 1.4 Hz, 1H).
Preparation Example 3
Synthesis of 5-cyanopyridin-2-carboxylic acid
[Formula 28]
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(1) Synthesis of methyl 5-cyanopyridin-2-carboxylate
A mixture of methyl 5-bromopyridine-2-carboxylate (2.8 g) and copper cyanide (3.6 g) in NMP (30 ml) was heated with stirring at 170 ° C for 1.5 hours. Water was added to the reaction solution at room temperature, and insoluble matter was removed by filtration. The filtrate was extracted with ethyl acetate. The extract was washed with brine and then dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography to obtain the title compound (920 mg).
1H-NMR (400 MHz, CDCl3) δ (ppm): 4.06 (s, 3H), 8.16 (dd, J = 2.0, 8.0 Hz, 1H), 8.27 (d, J = 8.0 Hz, 1H), 9.01 (d, J = 2.0 Hz, 1H).
(2) Synthesis of 5-cyanopyridin-2-carboxylic acid
A solution of the compound of Example 3- (1) of preparation (920 mg) and a 5 N solution of sodium hydroxide (2.26 ml) in ethanol (30 ml) was stirred at room temperature for 10 minutes. 5 N hydrochloric acid (5.2 ml) was added to the reaction solution at room temperature, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound (800 mg).
1H-NMR (400 MHz, DMSOd6) δ (ppm): 8.18 (d, J = 8.0 Hz, 1H), 8.51 (dd, J = 2.0, 8.0 Hz, 1H), 9.12-9.18 (m, 1 H).
Preparation Example 4
Synthesis of 5-difluoromethoxypyrazin-2-carboxylic acid
[Formula 29] image26
(1) Synthesis of methyl 5-difluoromethoxypyrazin-2-carboxylate
Potassium carbonate (8.82 g) and sodium chlorodifluoroacetate (6.53 g) were added to a solution of methyl 5-hydroxypyrazine-2-carboxylate (3.3 g) in DMF (42.8 ml). The reaction solution was stirred at 100 ° C for 30 minutes, and then saturated aqueous ammonium chloride was added, followed by extraction with ethyl acetate. The organic layer was washed with a solution of sodium bicarbonate and with brine, and then dried over magnesium sulfate. The drying agent was removed by filtration, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (928 mg).
1H-NMR (400 MHz, CDCl3) δ (ppm): 4.04 (s, 3H), 7.49 (t, J = 71.2 Hz, 1H), 8.47 (d, J = 0.8 Hz, 1H), 8.92 (d, J = 0.8 Hz, 1H).
(2) Synthesis of 5-difluoromethoxypyrazin-2-carboxylic acid
Water (1.54 ml) and a 5 N solution of sodium hydroxide (492 ml) were added to a solution of the compound obtained in Example 4- (1) of preparation (250 mg) in THF (4.60 ml) . The reaction solution was stirred at room temperature for five minutes, and then a 2N solution of hydrochloric acid was added, followed by extraction with ethyl acetate. The organic layer was washed with brine, and then dried over magnesium sulfate. The drying agent was removed by filtration, and then the solvent was concentrated under reduced pressure to obtain the title compound (200 mg).
1H-NMR (400 MHz, CDCl3) δ (ppm): 7.51 (t, J = 71.2 Hz, 1H), 8.39 (d, J = 1.2 Hz, 1H), 9.04 ( d, J = 1.2 Hz, 1H).
Preparation Example 5
Synthesis of (-) - [(4aR *, 8aS *) - 8a- (5-amino-2-trifluoromethoxyphenyl) -4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-2il] tert-butyl carbamate
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In Preparation Example 5, the compound obtained in Preparation Example 1- (2) was used as the starting material.
In Example 5- (1) and (2) of preparation, the synthesis was carried out according to Example 1- (3) and (4) of preparation.
(3) Synthesis of 1-benzoyl-3 - [(3S *, 4R *) - 4-hydroxymethyl-3- (2-trifluoromethoxyphenyl) tetrahydropyran-3-yl] thiourea
Benzoyl isothiocyanate (642 µl) was added to a solution of the compound obtained in the previous step (1.26 g) in dichloromethane (32.3 ml) at room temperature, and the mixture was stirred for two hours and 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (1.67 g).
1H-NMR (400 MHz, CDCl3) δ (ppm): 1.29-1.34 (m, 1H), 1.65-1.80 (m, 2H), 3.57-3.91 (m, 4H), 4.14-4.27 (m, 2H), 7.20-7.30 (m, 3H), 7.32-7.38 (m, 1H), 7.50-7.57 ( m, 2H), 7.61-7.67 (m, 1H), 7.86-7.92 (m, 1H), 8.92 (sa, 1H).
(4) Synthesis of N - [(4aR *, 8aS *) - 8a- (2-trifluoromethoxyphenyl) -4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen- 2il] benzamide
Concentrated hydrochloric acid (635 µl) was added to a solution of the compound obtained in the previous step (1.67 g) in methanol (25 ml), and the mixture was heated at reflux at 90 ° C for two hours and 10 minutes. The reaction solution was returned to room temperature and concentrated under reduced pressure. A solution of sodium bicarbonate was added to the residue, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure to obtain the title compound (1.65 g).
1H-NMR (400 MHz, CDCl3) δ (ppm): 1.53-1.68 (m, 1H), 2.22-2.35 (m, 1H), 2.62-2.71 (m, 1H), 2.91-2.99 (m, 1H), 3.19-3.29 (m, 1H), 3.62-3.78 (m, 2H), 4.07-4.21 ( m, 2H), 7.28-7.36 (m, 2H), 7.38-7.47 (m, 3H), 7.48-7.57 (m, 2H), 8.21-8, 27 (m, 2H).
(5) Synthesis of (4aR *, 8aS *) - 8a- (2-trifluoromethoxyphenyl) -4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-2-ylamine
DBU (1.28 ml) was added to a solution of the compound obtained in the previous step (1.65 g) in methanol (100 ml), and the mixture was heated at reflux at 80 ° C for eight hours and 10 minutes. The reaction solution was returned to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (870 mg).
1 H-NMR (400 MHz, CDCl 3) δ (ppm): 1.40-1.50 (m, 1H), 2.02-2.16 (m, 1H), 2.61-2.70 (m, 1H), 2.87-3.01 (m, 2H), 3.60-3.75 (m, 2H), 4.03-4.15 (m, 2H), 4.51 (sa, 2H) , 7.21-7.34 (m, 3H), 7.48-7.52 (m, 1H).
In Example 5- (6), (7) and (8) of preparation, the synthesis was carried out according to Example 1- (7) and (8) of preparation.
(9) Synthesis of (-) - [(4aR *, 8aS *) - 8a- (5-amino-2-trifluoromethoxyphenyl) -4,4a, 5,6,8,8a-hexahydro-7-oxa-3- tia-1-azanaphthalen2-yl] tert-butyl carbamate
The compound obtained in the previous step (12 mg) was purified by CHIRALPAK ™ AD-H (mobile phase: hexane: ethanol = 8: 2, flow rate: 10 ml / min.), And the fraction with a retention time of 15 at 20 minutes it was collected
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to get the title compound. This operation was repeated to obtain the title compound (112 mg;> 99% ee) from 240 mg of the racemate.
1H-NMR (400 MHz, CDCl3) δ (ppm): 1.53 (s, 9H), 1.54-1.60 (m, 1H), 2.13-2.27 (m, 1H), 2 , 51-2.60 (m, 1H), 2.90-2.96 (m, 1H), 3.03-3.12 (m, 1H), 3.58-3.67 (m, 2H) , 3.80 (sa, 2H), 4.05-4.17 (m, 2H), 6.60 (dd, J = 8.8, 2.8 Hz, 1H), 6.67 (d, J = 2.8 Hz, 1H), 7.06-7.11 (m, 1H).
Preparation Example 6
Synthesis of (-) - [(4aR *, 6S *, 8aS *) - 8a- (5-amino-2-fluorophenyl) -6-methyl-4,4a, 5,6,8,8a-hexahydro-7- tert-butyl oxa-3-thia-1-azanaphthalen2-yl] carbamate
[Formula 31] image28
(1) Synthesis of 4- (2,2-diethoxy-ethoxy) -1-pentene
60% Sodium hydride (916 mg) was added to a solution of 4-penten-2-ol (1.8 ml) in dimethylformamide (40 ml) at 0 ° C, followed by stirring for 30 minutes. After heating to room temperature, bromoacetaldehyde diethyl acetal (2.99 ml) was added to the reaction solution, and the mixture was heated for five hours. Ice was added to the reaction solution, followed by extraction with diethyl ether. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (1.95 g).

Ejemplo 4

Estructura química Nombre de compuesto: N-[3-((4aR*,8aS*)-2-amino-4,4a,5,6,8,8ahexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4-trifluorometoxifenil]-5cianopiridin-2-carboxamida

ESI-MS m/z 478 [M++H]

Ejemplo 5

Estructura química Nombre de compuesto: N-[3-((8S*,8aS*)-2-amino-4,4a,5,6,8,8ahexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4-trifluorometoxifenil]-5cloropiridin-2-carboxamida

ESI-MS m/z 487 [M++H]

Ejemplos 6 a 10
Los compuestos de los Ejemplos 6 a 10 más abajo se sintetizaron según el Ejemplo 2 usando el compuesto del 10 Ejemplo 6-(12) de preparación y los ácidos carboxílicos correspondientes, como se muestra en la siguiente Tabla 2.
[Tabla 2]

Ejemplo 6

Estructura química Nombre de compuesto: N-[3-((4aR*,6S*,8aS*)-2-amino-6-metil4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4fluorofenil]-5-cloropiridin-2-carboxamida

ESI-MS m/z 435 [M++H]

Ejemplo 7

Estructura química Nombre de compuesto: N-[3-((4aR*,6S*,8aS*)-2-amino-6-metil4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4fluorofenil]-5-cianopiridin-2-carboxamida

ESI-MS m/z 426 [M++H]

Ejemplo 8

Estructura química Nombre de compuesto: N-[3-((4aR*,6S*,8aS*)-2-amino-6-metil4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4fluorofenil]-5-trifluorometilpiridin-2-carboxamida

ESI-MS m/z 469 [M++H]

Ejemplo 9

Estructura química Nombre de compuesto: N-[3-((4aR*,6S*,8aS*)-2-amino-6-metil4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4fluorofenil]-5-difluorometoxipirazin-2-carboxamida

ESI-MS m/z 468 [M++H]

Ejemplo 10

Estructura química Nombre de compuesto: N-[3-((4aR*,6S*,8aS*)-2-amino-6-metil4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4fluorofenil]-5-fluorometoxipirazin-2-carboxamida

ESI-MS m/z 450 [M++H]

Ejemplos 11 a 15
Los compuestos de los Ejemplos 11 a 15 más abajo se sintetizaron según el Ejemplo 2 usando el compuesto del Ejemplo 7-(12) de preparación y los ácidos carboxílicos correspondientes, como se muestra en la siguiente Tabla 3.
[Tabla 3-1]

Ejemplo 11

Estructura química Nombre de compuesto: N-[3-((4aR*,6R*,8aS*)-2-amino-6-metoximetil4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]-5cianopiridin-2-carboxamida

1H-RMN (400MHz, CDCl3) δ (ppm): 1.45-1.53 (m, 1H), 1.80-1.93 (m, 1H), 2.58-2.67 (m, 1H), 2.94-3.07 (m, 2H), 3.43 (s, 3H), 3.43-3.57 (m, 2H), 3.81-3.92 (m, 2H), 4.14-4.21 (m, 1H), 7.02-7.11 (m, 1H), 7.35-7.41 (m, 1H), 7.97-8.06 (m, 1H), 8.16-8.23 (m, 1H), 8.37-8.44 (m, 1H), 8.868.91 (m, 1H), 9.80 (s a, 1H).

ESI-MS m/z 456 [M++H]

Ejemplo 12

Estructura química Nombre de compuesto: N-[3-((4aR*,6R*,8aS*)-2-amino-6-metoximetil4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]-5difluorometilpirazin-2-carboxamida

1H-RMN (400MHz, CDCl3) δ (ppm): 1.45-1.54 (m, 1H), 1.79-1.92 (m, 1H), 2.58-2.67 (m, 1H), 2.94-3.07 (m, 2H), 3.42 (s, 3H), 3.43-3.48 (m, 1H), 3.50-3.57 (m, 1H), 3.82-3.92 (m, 2H), 4.13-4.20 (m, 1H), 6.79 (t, J=54.6Hz, 1H), 7.02-7.10 (m, 1H), 7.35-7.41 (m, 1H), 7.96-8.04 (m, 1H), 8.88-8.93 (m, 1H), 9.47-9.52 (m, 1H), 9.60 (s a, 1H).

ESI-MS m/z 482 [M++H]

Ejemplo 13

Estructura química Nombre de compuesto: N-[3-((4aR*,6R*,8aS*)-2-amino-6-metoximetil4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]-5cloropiridin-2-carboxamida

ESI-MS m/z 465 [M++H]

[Tabla 3-2]

Ejemplo 14

Estructura química Nombre de compuesto: N-[3-((4aR*,6R*,8aS*)-2-amino-6-metoximetil4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]-5fluorometoxipirazin-2-carboxamida

ESI-MS m/z 480 [M++H]

Ejemplo 15

Estructura química Nombre de compuesto: N-[3-((4aR*,6R*,8aS*)-2-amino-6-metoximetil4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]-5difluorometoxipirazin-2-carboxamida

ESI-MS m/z 498 [M++H]

Ejemplos 16 a 30
Los compuestos de los Ejemplos 16 a 30 se sintetizaron según el Ejemplo 2 usando los ácidos carboxílicos correspondientes y los intermedios anilínicos correspondientes en los Ejemplos de Preparación, como se muestra en la siguiente Tabla 4.
[Tabla 4-1] [Tabla 4-2]

Ejemplo 16

Nombre de compuesto: N-[3-((4aS,5S,8aS)-2-amino-5-fluoro-4,4a,5,6,8,8ahexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]-5-cianopiridin-2carboxamida

1H-RMN (400MHz, CDCl3) δ (ppm): 2.87 (dd, J=4.0, 12.4Hz, 1H), 2.99-3.07 (m, 1H), 3.17 (dd, J=2.8, 12.8Hz, 1H), 3.53 (ddd, J=4.8, 10.4, 10.4Hz, 1H), 3.74 (dd, J=2.4, 11.2Hz, 1H), 4.08 (dd, J=2.0, 11.2Hz, 1H), 4.26 (dd, J=5.6, 10.4Hz, 1H), 4.18-5.01 (m, 1H), 7.11 (dd, J=8.8,11.6Hz, 1H), 7.42 (dd, J=2.8, 6.8Hz, 1H), 7.97 (ddd, J=2.8, 4.0, 8.4Hz, 1H), 8.20 (dd, J=2.4, 8.0Hz, 1H), 8.41 (dd, J=0.8, 8.0Hz, 1H), 8.88 (dd, J=0.8, 2.0Hz, 1H), 9.81 (s, 1H).

ESI-MS m/z 430 [M++H]

Ejemplo 17

Nombre de compuesto: N-[3-((4aS,5S,8aS)-2-amino-5-fluoro-4,4a,5,6,8,8ahexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]-5-difluorometilpirazin2-carboxamida

1H-RMN (400MHz, CDCl3) δ (ppm): 2.87 (dd, J=4.0, 12.8Hz, 1H), 2.99-3.07 (m, 1H), 3.17 (dd, J=3.2, 12.8Hz, 1H), 3.50-3.57 (m, 1H) 3.74 (dd, J=2.4, 10.8Hz, 1H), 4.08 (dd, J=2.0, 10.8Hz, 1H), 4.27 (dd, J=5.6, 10.4Hz, 1H), 4.80-5.00 (m, 1H), 6.80 (t, J=54.4Hz, 1H), 7.13 (dd, J=8.8,11.6Hz, 1H), 7.43 (dd, J=2.4, 6.4Hz, 1H), 7.95-7.99 (m, 1H), 8.93 (s, 1H), 9.52 (s, 1H), 9.62 (s, 1H).

ESI-MS m/z 456 [M++H]

Ejemplo 18

Nombre de compuesto: N-[3-((4aS,5S,8aS)-2-amino-5-fluoro-4,4a,5,6,8,8ahexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]-5-cloropiridin-2carboxamida

ESI-MS m/z 439 [M++H]

Ejemplo 19

Nombre de compuesto: N-[3-((4aS,5S,8aS)-2-amino-5-fluoro-4,4a,5,6,8,8ahexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]-5trifluorometilpiridin-2-carboxamida

ESI-MS m/z 473 [M++H]

Ejemplo 20

Nombre de compuesto: N-[3-((4aS,5S,8aS)-2-amino-5-fluoro-4,4a,5,6,8,8ahexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]-5difluorometoxipiridin-2-carboxamida

ESI-MS m/z 471 [M++H]

Ejemplo 21

Nombre de compuesto: N-[3-((4aS,5S,8aS)-2-amino-5-fluoro-4,4a,5,6,8,8ahexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]-5fluorometoxipirazin-2-carboxamida

ESI-MS m/z 454 [M++H]

Ejemplo 22

Nombre de compuesto: N-[3-((4aS,5S,8aS)-2-amino-5-fluoro-4,4a,5,6,8,8ahexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]-5difluorometoxipirazin-2-carboxamida

ESI-MS m/z 472 [M++H]

Ejemplo 23

Nombre de compuesto: N-[3-((4aR*,5S*,8aS*)-2-amino-5-metil4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]-5cloropiridin-2-carboxamida

ESI-MS m/z 435 [M++H]

[Tabla 4-3] [Tabla 4-4]

Ejemplo 24

Nombre de compuesto: N-[3-((4aR*,5S*,8aS*)-2-amino-5-metil 4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]-5cianopiridin-2-carboxamida

ESI-MS m/z 426 [M++H]

Ejemplo 25

imagen48 Nombre de compuesto: N-[3-((4aR*,5S*,8aS*)-2-amino-5-metil4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]-5difluorometoxipirazin-2-carboxamida

ESI-MS m/z 468 [M++H]

Ejemplo 26

Nombre de compuesto: N-[3-((4aR*,5R*,8aS*)-2-amino-5-metil4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]-5cloropiridin-2-carboxamida

ESI-MS m/z 435 [M++H]

Ejemplo 27

Nombre de compuesto: N-[3-((4aR*,5R*,8aS*)-2-amino-5-metil4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]-5cianopiridin-2-carboxamida

ESI-MS m/z 426 [M++H]

Ejemplo 28

Nombre de compuesto: N-[3-((4aR*,5R*,8aS*)-2-amino-5-metil4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]-5difluorometoxipirazin-2-carboxamida

ESI-MS m/z 468 [M++H]

Ejemplo 29

Nombre de compuesto: N-[3-((4aR*,5R*,8aS*)-2-amino-5-metil4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]-5difluorometilpirazin-2-carboxamida

ESI-MS m/z 452 [M++H]

Ejemplo 30

Nombre de compuesto: N-[3-((4aS*,5R*,8aS*)-2-amino-5-metoxi4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]-5cianopiridin-2-carboxamida

ESI-MS m/z 442 [M++H]

Ejemplo 31
5 Síntesis de N-[3-((2R*,4aR*,8aS*)-2-amino-4-metil-4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4fluorofenil]-5-cianopiridin-2-carboxamida imagen49
(1) Síntesis de (±)-((2R*,4aR*,8aS*)-8a-{5-[(5-cianopiridin-2-carbonil)-amino]-2-fluorofenil}-4-metil-4,4a,5,6,8,8ahexahidro-7-oxa-3-tia-1-azanaftalen-2-il)-carbamato de terc-butilo
10 Se añadió PyBOP (357 mg) a una disolución del compuesto obtenido en el Ejemplo 11-(10) de preparación (100 mg), el compuesto obtenido en el Ejemplo 3-(2) de preparación (56 mg) y N,N-diisopropiletilamina (143 l) en diclorometano (5 ml), y la mezcla se agitó a temperatura ambiente durante cinco horas. La disolución de la reacción se cargó directamente a un gel de sílice y se purificó mediante cromatografía en columna en gel de sílice para obtener el compuesto del título (100 mg).
ESI-MS; m/z 526 [M++H].
(2) Síntesis de (±)-((2R*,4aR*,8aS*)-8a-{5-[(5-cianopiridin-2-carbonil-amino]-2-fluorofenil}-4-metil-4,4a,5,6,8,8a5 hexahidro-7-oxa-3-tia-1-azanaftalen-2-il)-carbamato de terc-butilo
El compuesto obtenido en el Ejemplo 31-(1) se purificó mediante CHIRALPAK™ IB (fase móvil: hexano:etanol = 7:3, caudal: 10 ml/min.), y se recogió la fracción con un tiempo de retención de 23,4 a 26,7 minutos para obtener el compuesto del título. Se repitió la misma operación para obtener el compuesto del título (20 mg; >99% ee) a partir del material bruto (100 mg).
10 ESI-MS; m/z 526 [M++H].
(3) Síntesis de N-[3-((2R*,4aR*,8aS*)-2-amino-4-metil-4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4fluorofenil]-5-cianopiridin-2-carboxamida
Se añadió TFA (1 ml) a una disolución del compuesto obtenido en el Ejemplo 31-(2) (20 mg) en cloroformo (2 ml), y la mezcla se agitó a temperatura ambiente durante cinco horas. La disolución de la reacción se neutralizó con
15 bicarbonato de sodio saturado acuoso. Se añadió cloroformo a la mezcla, y la capa orgánica se separó. La capa orgánica se secó sobre sulfato de magnesio anhidro. La capa orgánica se concentró a presión reducida para obtener el compuesto del título (14 mg).
ESI-MS; m/z 426 [M++H].
Ejemplo 32
20 Síntesis de N-[3-((2R*,4aR*,8aS*)-2-amino-4-metil-4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4fluorofenil]-5-difluorometilpirazin-2-carboxamida imagen50
(1) Síntesis de (±)-((2R*,4aR*,8aS*)-8a-{5-[(5-difluorometilpirazin-2-carbonil)-amino]-2-fluoro-fenil}-4-metil4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-aza-naftalen-2-il)-carbamato de terc-butilo
25 El compuesto del título (132 mg) se obtuvo a partir del compuesto obtenido en el Ejemplo 11-(10) de preparación (100 mg) y el compuesto obtenido en el Ejemplo 12-(5) de preparación (56 mg) según el Ejemplo 31-(1).
ESI-MS; m/z 552 [M++H].
(2) Síntesis de (+1-((2R*,4aR*,8aS*)-8a-{5-[(5-difluorometilpirazin-2-carbonil)-amino]-2-fluoro-fenil}-4-metil4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-2-il)-carbamato de terc-butilo
30 El compuesto obtenido en el Ejemplo 32-(1) se purificó mediante CHIRALPAK™ IA (fase móvil: etanol, caudal: 10 ml/min.), y se recogió la fracción con un tiempo de retención de 10,8 a 13,5 minutos para obtener el compuesto del título. Se repitió la misma operación para obtener el compuesto del título (52 mg; >99% ee) a partir del material bruto (130 mg).
ESI-MS; m/z 552 [M++H].
35 (3) Síntesis de N-[3-((2R*,4aR*,8aS*)-2-amino-4-metil-4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4fluorofenil]-5-difluorometilpirazin-2-carboxamida
Se añadió TFA (1 ml) a una disolución del compuesto obtenido en el Ejemplo 32-(2) (52 mg) en cloroformo (3 ml), y la mezcla se agitó a temperatura ambiente durante cuatro horas. La disolución de la reacción se neutralizó con bicarbonato de sodio saturado acuoso. Se añadió cloroformo a la mezcla, y la capa orgánica se separó. La capa
40 orgánica se secó sobre sulfato de magnesio anhidro. La capa orgánica se concentró a presión reducida. El residuo se purificó mediante NH-cromatografía en columna en gel de sílice para obtener el compuesto del título (42 mg).
ESI-MS; m/z 452 [M++H].
Ejemplos 33 a 34
Los compuestos de los Ejemplos 33 a 34 se sintetizaron según el Ejemplo 2 usando los ácidos carboxílicos correspondientes y los intermedios anilínicos correspondientes en los Ejemplos de Preparación, como se muestra en la siguiente Tabla 5.
[Tabla 5]

Ejemplo 33

Estructura química Nombre de compuesto: N-[3-((4aR,6R,8aS)-2-amino-6-hidroximetil4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]-5cloropiridin-2-carboxamida

ESI-MS m/z 451 [M++H]

Ejemplo 34

Estructura química Nombre de compuesto: N-[3-((4aR,6R,8aS)-2-amino-6-hidroximetil4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]-5cianopiridin-2-carboxamida

ESI-MS m/z 442 [M++H]

Ejemplos 35 a 43
5
Los compuestos de los Ejemplos 35 a 43 se sintetizaron según el Ejemplo 2 usando los ácidos carboxílicos correspondientes y los intermedios anilínicos correspondientes en los Ejemplos de Preparación, como se muestra en la siguiente Tabla 6.
10 [Tabla 6-1]

Ejemplo 35

Estructura química Nombre de compuesto: N-[3-((4aR*,6R*,8aS*)-2-amino-6-trifluorometil4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]-5cianopiridin-2-carboxamida

1H-RMN (400MHz, CDCl3) δ (ppm): 1.69-1.73 (m, 1H), 2.12 (ddd, J=2.4, 12.4, 24.8Hz, 1H), 2.67 (dd, J=2.4, 12.4Hz, 1H), 2.99-3.07 (m, 2H), 3.95 (d, J=11.2Hz, 1H), 4.05-4.09 (m, 1H), 4.18 (d, J=2.0, 11.2Hz, 1H), 7.09 (dd, J=8.8, 11.6Hz, 1H), 7.40 (dd, J=2.8, 6.4Hz, 1H), 8.00-8.05 (m, 1H), 8.21 (dd, J=2.0, 8.0Hz, 1H), 8.42 (d, J=8.0Hz, 1H), 8.90 (s, 1H), 9.81 (s, 1H).

Ejemplo 36

Estructura química Nombre de compuesto: N-[3-((4aR*,6R*,8aS*)-2-amino-6-trifluorometil4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]-5difluorometoxipirazin-2-carboxamida

1H-RMN (400MHz, CDCl3) δ (ppm): 1.69-1.73 (m, 1H), 2.13 (ddd, J=2.4, 12.0, 24.8Hz, 1H), 2.67 (dd, J=2.4, 12.0Hz, 1H), 2.98-3.07 (m, 2H), 3.98 (d, J=10.8Hz, 1H), 4.04-4.11 (m, 1H), 4.17 (dd, J=2.0, 12.8Hz, 1H), 7.02 (dd, J=8.4, 11.6Hz, 1H), 7.38 (dd, J=2.8, 6.8Hz, 1H), 7.51 (t, J=71.2Hz, 1H), 7.91-7.95 (m, 1H), 8.27 (d, J=1.2Hz, 1H), 9.01 (d, J-1.2Hz, 1H), 9.37 (s, 1H).

[Tabla 6-2] [Tabla 6-3]

Ejemplo 37

Estructura química Nombre de compuesto: N-[3-((4aR*,6R*,8aS*)-2-amino-6-trifluorometil4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]-5fluoropiridin-2-carboxamida

ESI-MS m/z 473 [M++H]

Ejemplo 38

Estructura química Nombre de compuesto: N-[3-((4aR*,6R*,8aS*)-2-amino-6-trifluorometil4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]piridin-2-carboxamida

ESI-MS m/z 455 [M++H]

Ejemplo 39

Estructura química Nombre de compuesto: N-[3-((4aR*,6R*,8aS*)-2-amino-6-trifluorometil4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]-5fluorometoxipirazin-2-carboxamida

ESI-MS m/z 504 [M++H]

Ejemplo 40

Estructura química Nombre de compuesto: N-[3-((4aR*,6R*,BaS*)-2-amino-6-trifluorometil4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]pirimidin-4-carboxamida

ESI-MS m/z 456 [M++H]

Ejemplo 41

Estructura química Nombre de compuesto: N-[3-((4aR*,6R*,8aS*)-2-amino-6-trifluorometil4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]3.5-difluoropiridin-2-carboxamida

ESI-MS m/z 491 [M++H]

Ejemplo 42

Estructura química Nombre de compuesto: N-[3-((4aR*,6R*,8aS*)-2-amino-6-trifluorometil4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]-5difluorometoxipiridin-2-carboxamida

1H-RMN (400MHz, CDCl3) δ (ppm): 1.68-1.73 (m, 1H), 2.13 (ddd, J=2.8, 12.4, 25.2Hz, 1H), 2.66 (dd, J=2.8, 12.4Hz, 1H), 2.98-3.03 (m, 1H), 3.06 (dd, J=4.4, 12.4Hz, 1H), 3.97 (d, J=10.8Hz, 1H), 4.04-4.13 (m, 1H), 4.18 (dd, J=2.0, 10.8Hz, 1H), 6.65 (t, J=71.6Hz, 1H), 7.03 (dd, J=8.8, 12.0Hz, 1H), 7.38 (dd, J=2.8, 7.2Hz, 1H), 7.65 (dd, J=2.8, 8.8Hz, 1H), 7.97-8.00 (m, 1H), 8.28 (d, J=8.8Hz, 1H), 8.43 (d, J=2.4Hz, 1H), 9.75 (s, 1H).

[Tabla 6-4]

Ejemplo 43

Estructura química Nombre de compuesto: N-[3-((4aR*,6R*,8aS*)-2-amino-6-trifluorometil4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]-5difluorometilpirazin-2-carboxamida

1H-RMN (400MHz, CDCl3) δ (ppm): 1.69-1.74 (m, 1H), 2.12 (ddd, J=2.4, 12.0, 24.8Hz, 1H), 2.68 (dd, J=2.8, 12.4Hz, 1H), 2.99-3.08 (m, 2H), 3.95 (d, J=11.2Hz, 1H), 4.05-4.11 (m, 1H), 3.18 (dd, J=2.0, 10.8Hz, 1H), 6.80 (t, J=54.4Hz, 1H), 7.09 (dd, J=8.8, 12.0Hz, 1H), 7.41 (dd, J=2.8, 7.2Hz, 1H), 7.97-8.01 (m, 1H), 8.91 (d, J=0.8Hz, 1H), 9.51 (t, J=0.8Hz, 1H), 9.60 (s, 1H).

Ejemplos 44 a 48
Los compuestos de los Ejemplos 44 a 48 se sintetizaron según el Ejemplo 2 usando los ácidos carboxílicos correspondientes y los intermedios anilínicos correspondientes en los Ejemplos de Preparación, como se muestra en la siguiente Tabla 7.
[Tabla 7-1] [Tabla 7-2]

Ejemplo 44

Estructura química Nombre de compuesto: N-[3-((4aR,6R,8aS)-2-amino-6-fluorometil4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]-5cianopiridin-2-carboxamida

ESI-MS m/z 444 [M++H]

Ejemplo 45

Estructura química Nombre de compuesto: N-[3-((4aR,6R,8aS)-2-amino-6-fluorometil4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]-5cloropiridin-2-carboxamida

ESI-MS m/z 453 [M++H]

Ejemplo 46

Estructura química Nombre de compuesto: N-[3-((4aR,6R,8aS)-2-amino-6-fluorometil4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]-5trifluorometilpiridin-2-carboxamida

ESI-MS m/z 487 [M++H]

Ejemplo 47

Estructura química Nombre de compuesto: N-[3-((4aR,6R,8aS)-2-amino-6-fluorometil4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]-5fluorometoxipirazin-2-carboxamida

1H-RMN (400MHz, CDCl3) δ (ppm): 1.49-1.54 (m, 1H), 1.83-1.92 (m, 1H), 2.63 (dd, J=2.4, 12.4Hz, 1H), 3.00-3.07 (m, 2H), 3.90 (d, J=11.2Hz, 1H), 3.93-4.00 (m, 1H), 4.16 (dd, J=1.6, 11.2Hz, 1H), 4.35-4.58 (m, 2H), 6.09 (dd, J=2.0, 3.6Hz, 1H), 6.21 (dd, J=2.0, 4.0Hz, 1H), 7.06 (dd, J=8.8, 12.0Hz, 1H), 7.35 (dd, J=2.4, 6.4Hz, 1H), 7.97-8.01 (m, 1H), 8.27 (d, J=0.8Hz, 1H), 9.06 (t, J=0.8Hz, 1H), 9.45 (s, 1H).

Ejemplo 48

Estructura química Nombre de compuesto: N-[3-((4aR,6R,8aS)-2-amino-6-fluorometil4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]-5difluorometilpirazin-2-carboxamida

1H-RMN (400MHz, CDCl3) δ (ppm): 1.49-1.54 (m, 1H), 1.83-1.92 (m, 1H), 2.65 (dd, J=2.8, 12.4Hz, 1H), 3.00-3.07 (m, 2H), 3.89 (d, J=10.8Hz, 1H), 3.93-4.00 (m, 1H), 4.17 (dd, J=2.0, 10.8Hz, 1H), 3.45-4.59 (m, 2H), 6.76 (t, J=54.8Hz, 1H), 7.08 (dd, J=8.8, 12.0Hz, 1H), 7.40 (dd, J=2.8, 6.4Hz, 1H), 7.97-8.01 (m, 1H), 8.91 (d, J=1.2Hz, 1H), 9.51 (d, J=1.2Hz, 1H), 9.60 (s, 1H).

Ejemplos 49 a 58
Los compuestos de los Ejemplos 49 a 58 se sintetizaron según el Ejemplo 2 usando los ácidos carboxílicos correspondientes y los intermedios anilínicos correspondientes en los Ejemplos de Preparación, como se muestra en la siguiente Tabla 8.
[Tabla 8-1] [Tabla 8-2]

Ejemplo 49

Estructura química Nombre de compuesto: N-[3-((4aR*,8aS*)-2-amino-4,4a,5,6,8,8ahexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]-5-cloropiridin-2carboxamida

1H-RMN (400MHz, CDCl3) δ (ppm): 1.45 (dd, J=2.0, 13.6Hz, 1H), 2.102.20 (m, 1H), 2.63 (dd, J=2.8, 12.4Hz, 1H), 2.92-2.96 (m, 1H), 3.02 (dd, J=4.4, 12.8Hz, 1H), 3.66-3.72 (m, 1H), 3.80 (d, J=10.8Hz, 1H), 4.04-4.15 (m, 2H), 7.05 (dd, J=8.8, 11.6Hz, 1H), 7.37 (dd, J=2.8, 6.8Hz, 1H), 7.87 (dd, J=2.0, 8.4Hz, 1H), 7.97-8.01 (m, 1H), 8.21 (d, J=8.4Hz, 1H), 8.53 (d, J=2.0Hz, 1H), 9.77 (s, 1H).

Ejemplo 50

Estructura química Nombre de compuesto: N-[3-((4aR*,8aS*)-2-amino-4,4a,5,6,8,8ahexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]-5-bromopiridin-2carboxamida

1H-RMN (400MHz, CDCl3) δ (ppm): 1.45 (d, J=12.8Hz, 1H), 2.10-2.19 (m, 1H), 2.65 (dd, J=2.4, 12.4Hz, 1H), 2.93-2.97 (m, 1H), 3.03 (dd, J=4.0, 12.0Hz, 1H), 3.69 (t, J=12.0Hz, 1H), 3.79 (d, J=10.8Hz, 1H), 4.05-4.14 (m, 2H), 7.07 (dd, J=8.8, 12.0Hz, 1H), 7.36-7.39 (m, 1H), 7.98-8.05 (m, 2H). 8.16 (d, J=8.0, 1H), 8.66 (s, 1H), 9.79 (s, 1H).

Ejemplo 51

Estructura química Nombre de compuesto: N-[3-((4aR*,8aS*)-2-amino-4,4a,5,6,8,8ahexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]-3.5-difluoropiridin2-carboxamida

1H-RMN (400MHz, CDCl3) δ (ppm): 1.45 (dt, J=2.0, 13.6Hz, 1H). 2.052.19 (m, 1H). 2.64 (dd, J=3.2, 12.4Hz, 1H), 2.91-2.97 (m, 1H), 3.02 (dd, J=4.0, 12.0Hz, 1H), 3.65-3.72 (m, 1H), 3.78 (d, J=10.8Hz, 1H), 4.03-4.15 (m, 2H), 7.06 (dd, J=8.8, 12.0Hz, 1H), 7.24-7.27 (m, 1H), 7.36-7.41 (m, 1H), 8.05-8.09 (m, 1H), 8.33 (d, J=2.0Hz, 1H), 9.56 (s, 1H).

Ejemplo 52

Estructura química Nombre de compuesto: N-[3-((4aR*,8aS*)-2-amino-4,4a,5,6,8,8ahexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]-3.5-dicloropiridin2-carboxamida

1H-RMN (400MHz, CDCl3) δ (ppm): 1.43-1.47 (m, 1H), 2.08-2.19 (m, 1H), 2.64 (dd, J=3.2, 12.4Hz, 1H), 2.92-2.97 (m, 1H), 3.01 (dd, J=4.4, 12.4Hz, 1H), 3.65-3.71 (m, 1H), 3.76 (d, J=11.2Hz, 1H), 4.03-4.11 (m, 2H), 7.07 (dd, J=9.2, 12.0Hz, 1H), 7.19 (dd, J=2.8, 6.8Hz, 1H), 7.90 (d, J=2.0Hz, 1H), 8.11-8.15 (m, 1H), 8.46 (d, J=2.0Hz, 1H), 9.68 (s, 1H).

[Tabla 8-3] [Tabla 8-4]

Ejemplo 53

Estructura química Nombre de compuesto: N-[3-((4aR*,8aS*)-2-amino-4,4a,5,6,8,8ahexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]-5-fluoropiridin-2carboxamida

1H-RMN (400MHz, CDCl3) δ (ppm): 1.43-1.47 (m, 1H), 2.09-2.20 (m, 1H), 2.63 (dd, J=2.8, 12.0Hz, 1H), 2.91-2.97 (m, 1H), 3.02 (dd, J=4.0, 12.0Hz, 1H), 3.65-3.72 (m, 1H), 3.79 (d, J=10.8Hz, 1H), 4.04-4.12 (m, 2H), 7.06 (dd, J=8.8, 11.6Hz, 1H), 7.3 (dd, J=2.4, 6.4Hz, 1H), 7.59 (dt, J=2.4, 8.4Hz, 1H), 7.99-8.03 (m, 1H), 8.31 (dd, J=4.4, 8.4Hz, 1H), 8.44 (d, J=2.8Hz, 1H), 9.76 (s, 1H).

Ejemplo 54

Estructura química Nombre de compuesto: N-[3-((4aR*,8aS*)-2-amino-4,4a,5,6,8,8ahexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]-3.5dibromopiridin-2-carboxamida

ESI-MS m/z 545 [M++H]

Ejemplo 55

Estructura química Nombre de compuesto: N-[3-((4aR*,8aS*)-2-amino-4,4a,5,6,8,8ahexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]-5trifluorometilpiridin-2-carboxamida

1H-RMN (400MHz, CDCl3) δ (ppm):.1.43-1.47 (m, 1H), 2.10-2.19 (m, 1H), 2.65 (dd, J=3.2, 12.4Hz, 1H), 2.92-2.97 (m, 1H), 3.03 (dd, J=4.0, 12.0Hz, 1H), 3.66-3.72 (m, 1H), 3.79 (d, J=11.2Hz, 1H), 4.05-4.12 (m, 2H), 7.08 (dd, J=8.8, 12.0Hz, 1H), 7.39 (dd, J=2.8, 6.4Hz, 1H), 8.00-8.04 (m, 1H), 8.16 (dd, J=1.6, 8.4Hz, 1H), 8.42 (d, J=8.0Hz, 1H), 8.88 (t, J=0.8Hz, 1H), 9.89 (s, 1H).

Ejemplo 56

Estructura química Nombre de compuesto: N-[3-((4aR*,8aS*)-2-amino-4,4a,5,6,8,8ahexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]-5difluorometilpiridin-2-carboxamida

1H-RMN (400MHz, CDCl3) δ (ppm): 1.43-1.47 (m, 1H), 2.09-2.21 (m, 1H). 2.64 (dd, J=2.8, 12.0Hz, 1H), 2.92-2.98 (m, 1H), 3.02 (dd, J=8.0, 12.4Hz, 1H), 3.66-3.72 (m, 1H), 3.81 (d, J=10.8Hz, 1H), 4.05-4.15 (m, 2H), 6.81 (t, J=55.6Hz, 1H), 7.05 (dd, J=9.2, 12.0Hz, 1H), 8.40 (dd, J=2.8, 6.8Hz, 1H), 7.98-8.06 (m, 2H), 8.36 (d, J=8.4Hz, 1H), 8.73 (s, 1H), 9.90 (s, 1H).

[Tabla 8-5]

Ejemplo 57

Estructura química Nombre de compuesto: N-[3-((4aR*,8aS*)-2-amino-4,4a,5,8,8a-hexahidro7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]-5-difluorometilpirazin-2carboxamida

1H-RMN (400MHz, CDCl3) δ (ppm): 1.44-1.48 (m, 1H), 2.10-2.19 (m, 1H), 2.65 (dd, J=2.8, 12.0Hz, 1H), 2.93-3.04 (m, 2H), 3.66-3.72 (m, 1H), 3.80 (d, J=11.2Hz, 1H), 4.04-4.15 (m, 2H), 6.79 (t, J=54.4Hz.1H). 7.08 (dd, J=8.8, 12.0Hz, 1H), 7.40 (dd, J=2.8, 6.4Hz, 1H), 7.97-8.01 (m, 1H), 8.90 (d, J=0.8Hz, 1H), 9.50 (s, 1H), 9.60 (s, 1H).

Ejemplo 58

Estructura química Nombre de compuesto: N-[3-((4aR*,8aS*)-2-amino-4,4a,5,6,8,8ahexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]-5difluorometoxipiridin-2-carboxamida

1H-RMN (400MHz, CDCl3) δ (ppm): 1.43-1.47 (m, 1H), 2.05-2.20 (m, 1H), 2.63 (dd, J=2.8, 12.0Hz, 1H), 2.91-2.97 (m, 1H), 3.03 (dd, J=4.0, 12.4Hz, 1H), 3.65-3.72 (m, 1H), 8.79 (d, J=11.2Hz, 1H), 4.04-4.13 (m, 2H), 6.65 (t, J=72.0Hz, 1H), 7.07 (dd, J=8.8, 12.0Hz, 1H). 7.36 (dd, J=3.2, 7.2Hz, 1H), 7.66 (dd, J=3.2, 8.8Hz, 1H), 8.00-8.04 (m, 1H), 8.31 (d, J=9.2Hz, 1H), 8.46 (d, J=2.4Hz, 1H), 9.80 (s, 1H).

Ejemplo 59
Síntesis de (±)-(4aR*,6R*,8aS*)-8a-[2-fluoro-5-(2-fluoropiridin-3-il)fenil]-6-trifluorometil-4,4a,5,6,8,8a-hexahidro-7-oxa3-tia-1-azanaftalen-2-ilamina
[Fórmula 53] imagen51
10 Se añadieron ácido 2-fluoropiridin-3-borónico (63,9 mg), tetraquis(trifenilfosfina)paladio (26,2 mg) y una disolución 1 N de carbonato de sodio (453 l) a una disolución de (±)-N,N-di(terc-butiloxicarbonil)-[(4aR*,6R*,8aS*)-8a-(5-bromo2-fluorofenil)-6-trifluorometil-4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-2-il]amina (138 mg) en DMF (9,9 ml), y la mezcla se agitó en una atmósfera de nitrógeno a 85ºC durante siete horas. La disolución de la reacción se enfrió hasta la temperatura ambiente y después se diluyó con acetato de etilo. La capa orgánica se lavó con agua y con salmuera. La capa orgánica se secó sobre sulfato de magnesio anhidro, y el disolvente se evaporó a presión reducida. Se añadieron diclorometano (4,0 ml) y TFA (1,0 ml) al residuo, y la mezcla se agitó a temperatura
5 ambiente durante cuatro horas. Cuando la reacción se terminó, la disolución de la reacción se diluyó con diclorometano, y se añadió hielo, seguido de neutralización con una disolución de bicarbonato de sodio. La capa acuosa se extrajo con cloroformo, y la capa orgánica se secó sobre sulfato de magnesio anhidro. El disolvente se evaporó a presión reducida, y el residuo se purificó mediante NH-cromatografía en columna en gel de sílice. El sólido blanco resultante se lavó con éter dietílico para obtener el compuesto del título (14,0 mg).
10 1H-RMN (400 MHz, CDCl3) δ (ppm): 1,68-1,72 (m, 1H), 2,12 (ddd, J = 2,8, 12,0, 24,8 Hz, 1H), 2,68 (dd, J = 2,4, 12,4 Hz, 1H), 2,99-3,08 (m, 2H), 3,96 (d, J = 11,6 Hz, 1H), 4,06-4,11 (m, 1H), 4,20 (dd, J = 2,0, 11,2 Hz, 1H), 7,15 (dd, J = 8,8, 12,4 Hz, 1H), 7,25-7,30 (m, 1H), 7,50-7,54 (m, 2H), 7,83 (ddd, J = 1,6, 7,2, 9,2 Hz, 1H), 8,19-8,21 (m, 1H).
Ejemplo 60
Síntesis de (4aR,6R,8aS)-8a-[2-fluoro-5-(2-fluoropiridin-3-il)fenil]-6-fluorometil-4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-115 azanaftalen-2-ilamina
[Fórmula 54] imagen52
Se añadieron ácido 2-fluoropiridin-3-borónico (51,1 mg), tetraquis(trifenilfosfina)paladio (19,1 mg) y una disolución 1 N de carbonato de sodio (363 l) a una disolución de N,N-di(terc-butiloxicarbonil)-[(4aR,6R,8aS)-8a-(5-bromo-220 fluorofenil)-6-fluorometil-4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-2-il]amina (95 mg) en DMF (6,79 ml). Después de sustituir con nitrógeno, la mezcla se agitó a 85ºC durante dos horas. Después de enfriar hasta la temperatura ambiente, la mezcla se diluyó con agua. La capa acuosa se extrajo con acetato de etilo, y la capa orgánica se lavó con agua. La capa orgánica se secó sobre sulfato de magnesio anhidro, y el disolvente se evaporó a presión reducida. El residuo se purificó mediante cromatografía en columna en gel de sílice. El intermedio
25 resultante se disolvió en diclorometano (4,0 ml). Se añadió TFA (1,0 ml), y la mezcla se agitó a temperatura ambiente durante tres horas. Se añadió hielo a la mezcla de reacción, seguido de neutralización con una disolución de bicarbonato de sodio. La capa acuosa se extrajo con cloroformo, y la capa orgánica se secó sobre sulfato de magnesio anhidro. El disolvente se evaporó a presión reducida, y el residuo se purificó mediante cromatografía en columna en gel de sílice para obtener el compuesto del título (59,0 mg).
30 1H-RMN (400 MHz, CDCl3) δ (ppm): 1,48-1,53 (m, 1H), 1,82-1,92 (m, 1H), 2,63-2,66 (m, 1H), 2,98-3,07 (m, 2H), 3,89 (d, J = 10,8 Hz, 1H), 3,93-4,01 (m, 1H), 4,17-4,20 (m, 1H), 4,35-4,58 (m, 2H), 7,14 (dd, J = 8,0, 12,0 Hz, 1H), 7,257,22 (m, 1H), 7,48-7,55 (m, 2H), 7,78-7,83 (m, 1H), 8,16-8,18 (m, 1H).
Ejemplo 61
Síntesis de (±)-(4aR*,8aS*)-8a-[2-fluoro-5-(2-fluoropiridin-3-il)fenil]-4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-135 azanaftalen-2-ilamina
[Fórmula 55] imagen53
Se añadieron ácido 2-fluoropiridin-3-borónico (25,6 mg), tetraquis(trifenilfosfina)paladio (10,5 mg) y una disolución 1 N de carbonato de sodio (182 l) a una disolución de (±)-N-benzoil-N-(terc-butiloxicarbonil)-[(4aR*,8aS*)-8a-(540 bromo-2-fluorofenil)-4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-2-il]amina (50 mg) en DMF (5,0 ml). Después de sustituir con nitrógeno, la mezcla se agitó a 90ºC durante seis horas. La disolución de la reacción se enfrió hasta la temperatura ambiente y se diluyó con agua. La capa acuosa se extrajo con acetato de etilo. La capa orgánica se lavó con agua y con salmuera y se secó sobre sulfato de magnesio anhidro. El disolvente se evaporó a presión reducida, y el residuo se purificó mediante NH-cromatografía en columna en gel de sílice para obtener el compuesto
45 del título (12,7 mg).
1H-RMN (400 MHz, CDCl3) δ (ppm): 1,43-1,47 (m, 1H), 2,08-2,20 (m, 1H), 2,66 (dd, J = 2,8, 12,0 Hz, 1H), 2,90-2,96 (m, 1H), 3,01 (dd, J = 4,0, 12,4 Hz, 1H), 3,69 (dt, J = 2,8, 12,4 Hz, 1H), 3,79 (d, J = 11,2 Hz, 1H), 4,07-4,13 (m, 2H), 4,60 (s a, 2H), 7,14 (dd, J = 8,4, 12,0 Hz, 1H), 7,25-7,28 (m, 1H), 7,48-7,55 (m, 2H), 7,81-7,86 (m, 1H), 8,18-8,20 (m, 1H).
Ejemplos 62 a 63
Los compuestos de los Ejemplos 62 a 63 se sintetizaron según el Ejemplo 61 usando los ácidos borónicos correspondientes, como se muestra en la siguiente Tabla 9.
[Tabla 9]

Ejemplo 62

Estructura química Nombre de compuesto: (±)-(4aR*,8aS*)-8a-(2-fluoro-5-pirimidin-5-ilfenil)4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-2-ilamina

imagen54

ESI-MS m/z 345 [M++H]

Ejemplo 63

Estructura química Nombre de compuesto: (±)-(4aR*,8aS*)-8a-[5-(5-cloropiridin-3-il)-2fluorofenil]-4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-2-ilamina

ESI-MS m/z 378 [M*+H]

10 Ejemplo 64 Síntesis de N-[5-((4aR*,8aS*)-2-amino-4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)tiofen-3-il]-5cianopiridin-2-carboxamida [Fórmula 56] imagen55
15 Se añadieron secuencialmente ácido 5-cianopiridin-2-carboxílico (19,0 mg), diisopropiletilamina (50,7 l) y PyBOP (83,5 mg) a una disolución de (+)-N,N-di(terc-butiloxicarbonil)-[(4aR*,8aS*)-8a-(4-aminotiofen-2-il)-4,4a,5,6,8,8ahexahidro-7-oxa-3-tia-1-azanaftalen-2-il]amina (50 mg) en diclorometano (5,0 ml) en un baño de hielo. La mezcla se devolvió a la temperatura ambiente y se agitó toda la noche. El disolvente se evaporó a presión reducida, y el residuo se purificó mediante NH-cromatografía en columna en gel de sílice. El intermedio resultante se disolvió en
20 diclorometano (4,0 ml), y se añadió TFA (1,0 ml). Después de agitar a temperatura ambiente durante cuatro horas, se añadió hielo para terminar la reacción. La mezcla se neutralizó con una disolución de bicarbonato de sodio, y la capa acuosa se neutralizó con acetato de etilo. La capa orgánica se secó sobre sulfato de magnesio anhidro, y el disolvente se evaporó a presión reducida. El residuo se purificó mediante NH-cromatografía en columna en gel de sílice para obtener el compuesto del título (33,9 mg).
25 ESI-MS m/z 400 [M++H]
Ejemplo 65
Síntesis de (±)-(4aR*,8aR*)-8a-[4-(2-fluoropiridin-3-il)-tiofen-2-il]-4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-2ilamina
[Fórmula 57] imagen56
5
Se añadieron secuencialmente ácido 2-fluoropiridin-3-borónico (26,9 mg), tetraquis(trifenilfosfina)paladio (11,0 mg) y una disolución 1 N de carbonato de sodio (191 l) a una disolución de (±)-N,N-di-(terc-butiloxicarbonil)-[(4aR*,8aS*)8a-(4-bromotiofen-2-il)-4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-2-il]amina obtenida en el Ejemplo 19-(3) de preparación (51,0 mg) en DMF (2,0 ml). Después de sustituir con nitrógeno, la mezcla se agitó a 80ºC durante cinco 10 horas. La disolución de la reacción se devolvió a la temperatura ambiente y se diluyó con agua. La capa acuosa se extrajo con acetato de etilo, y la capa orgánica se lavó con agua. La capa orgánica se secó sobre sulfato de magnesio anhidro, y el disolvente se evaporó a presión reducida. El residuo se purificó mediante cromatografía en columna en gel de sílice para obtener un intermedio. El intermedio resultante se disolvió en diclorometano (5,0 ml). Se añadió TFA (2,0 ml), y la mezcla se agitó a temperatura ambiente durante tres horas. Se añadió hielo a la
15 mezcla, seguido de neutralización con una disolución de bicarbonato de sodio. La capa acuosa se extrajo con acetato de etilo, y la capa orgánica se secó sobre sulfato de magnesio anhidro. El disolvente se evaporó a presión reducida, y el residuo se purificó mediante NH-cromatografía en columna en gel de sílice para obtener el compuesto del título (22,0 mg).
ESI-MS m/z 350 [M++H]
20 Ejemplo 66
Síntesis de (4aR,6R,8aS)-8a-[2-fluoro-5-(2-fluoropiridin-3-il)fenil]-6-benciloximetil-4,4a,5,6,8,8a-hexahidro-7-oxa-3tia-1-azanaftalen-2-ilamina
[Fórmula 58] imagen57
25 Se añadieron ácido 2-fluoropiridin-3-borónico (44,0 mg), tetraquis(trifenilfosfina)paladio (18,0 mg) y una disolución 1 N de carbonato de sodio (312 l) a una disolución de N,N-di-(terc-butiloxicarbonil)-[(4aR,6R,8aS)-8a-(5-bromo-2fluorofenil)-6-benciloximetil-4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-2-il]amina (95 mg) en DMF (6,79 ml). Después de sustituir con nitrógeno, la mezcla se agitó a 85ºC durante siete horas. Después de enfriar hasta la temperatura ambiente, la mezcla se diluyó con agua. La capa acuosa se extrajo con acetato de etilo, y la capa
30 orgánica se lavó con agua. La capa orgánica se secó sobre sulfato de magnesio anhidro, y el disolvente se evaporó a presión reducida. El residuo se purificó mediante cromatografía en columna en gel de sílice. El intermedio resultante se disolvió en diclorometano (4,0 ml). Se añadió TFA (1,0 ml), y la mezcla se agitó a temperatura ambiente durante tres horas. Se añadió hielo a la mezcla de reacción, seguido de neutralización con una disolución de bicarbonato de sodio. La capa acuosa se extrajo con cloroformo, y la capa orgánica se secó sobre sulfato de
35 magnesio anhidro. El disolvente se evaporó a presión reducida, y el residuo se purificó mediante cromatografía en columna en gel de sílice para obtener el compuesto del título (23,0 mg).
ESI-MS m/z 482 [M++H]
Ejemplo 67
Síntesis de (±)-N-[7-((4aR*,8aS*)-2-amino-4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-2,2difluorobenzo[1,3]dioxol-5-il]-5-cianopiridin-2-carboxamida
[Fórmula 59] imagen58
5 Se añadieron ácido 5-cianopiridin-2-carboxílico (4,0 mg), diisopropiletilamina (11,5 l) y PyBOP (17,6 mg) a una disolución de (±)-[(4aR*,8aS*)-8a-(6-amino-2,2-difluorobenzo[1,3]dioxol-4-il)-4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1azanaftalen-2-il]carbamato de terc-butilo (10 mg) en diclorometano (2,0 ml) en un baño de hielo. La mezcla se calentó hasta la temperatura ambiente y se agitó durante cuatro horas. El disolvente se evaporó a presión reducida, y el residuo se purificó mediante NH-pTLC para obtener un intermedio. El intermedio resultante se disolvió en
10 diclorometano (3,0 ml), y se añadió TFA (1,0 ml). Después de agitar a temperatura ambiente durante cuatro horas, la disolución de la reacción se diluyó con agua y se neutralizó con una disolución de bicarbonato de sodio. La capa acuosa se extrajo con diclorometano, y la capa orgánica se secó sobre sulfato de magnesio anhidro. El disolvente se evaporó a presión reducida, y el residuo se purificó mediante NH-pTLC para obtener el compuesto del título.
1H-RMN (400 MHz, CDCl3) δ (ppm): 1,51-1,53 (m, 1H), 2,15 (ddd, J = 5,2, 13,2, 26,0 Hz, 1H), 2,71 (dd, J = 2,8, 12,4
15 Hz, 1H), 2,86-2,90 (m, 1H), 3,07 (dd, J = 4,4, 12,4 Hz, 1H), 3,68-3,73 (m, 1H), 3,85-3,91 (m, 2H), 4,11-4,15 (m, 1H), 7,03 (d, J = 2,0 Hz, 1H), 8,07 (d, J = 2,0 Hz, 1H), 8,21 (dd, J = 2,0, 8,0 Hz, 1H), 8,41 (dd, J = 0,8, 8,0 Hz, 1H), 8,92 (dd, J = 0,8, 2,0 Hz, 1H), 9,94 (s a, 1H).
Ejemplos 68 a 73
Los compuestos de los Ejemplos 68 a 73 se sintetizaron según el Ejemplo 2 usando los ácidos carboxílicos
20 correspondientes y los intermedios anilínicos correspondientes en los Ejemplos de Preparación, como se muestra en la siguiente Tabla 10.
[Tabla 10-1] [Tabla 10-2]

Ejemplo 68

Estructura química Nombre de compuesto: N-[3-((4aR*,8aS*)-2-amino-4,4a,5,6,8,8a-hexahidro7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]-5-(2-metoxietoxi)-pirazin-2carboxamida

1H-RMN (400MHz, CDCl3) δ (ppm): 1.40-1.50 (m, 1H), 2.01-2.21 (m, 1H), 2.59-2.68 (m, 1H), 2.88-2.98 (m, 1H), 2.98-3.06 (m, 1H), 3.46 (s, 3H), 3.633.73 (m, 1H), 3.73-3.84 (m, 3H), 4.01-4.12 (m, 2H), 4.55-4.65 (m, 2H), 7.027.11 (m, 1H), 7.29-7.35 (m, 1H), 7.98-8.06 (m, 1H), 8.19-8.24 (m, 1H), 8.969.01 (m, 1H), 9.46 (s a, 1H).

ESI-MS m/z 462 [M++H]

Ejemplo 69

Estructura química Nombre de compuesto: N-[3-((4aR*,8aS*)-2-amino-4,4a,5,6,8,8a-hexahidro7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]-2-metiltiazol-4-carboxamida

1H-RMN (400MHz, CDCl3) δ (ppm): 1.39-1.50 (m, 1H), 2.06-2.21 (m, 1H), 2.59-2.67 (m, 1H), 2.76 (s, 3H), 2.89-2.97 (m, 1H), 2.98-3.07 (m, 1H), 3.623.73 (m, 1H), 3.73-3.81 (m, 1H), 4.01-4.13 (m, 2H), 7.02-7.10 (m, 1H), 7.287.34 (m, 1H), 7.93-7.99 (m, 1H), 8.04 (s, 1H), 9.17 (s a, 1H).

ESI-MS m/z 407 [M++H]

Ejemplo 70

Estructura química Nombre de compuesto: N-[3-((4aR*, 5R*, 8aS*) Nombre de compuesto: N-[3((4aR*,5R*,8aS*)-2-amino-5-metil-4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1azanaftalen-8a-il)-4-fluorofenil]-2,5-dimetilfuran-3-carboxamida

1H-RMN (400MHz, CDCl3) δ (ppm): 0.94 (d, J=6.8Hz, 3H), 2.21-2.27 (m, 1H), 2.28 (s, 3H), 2.58 (s, 3H), 2.61-2.68 (m, 1H), 2.93-2.96 (m, 2H), 3.25-3.36 (m, 1H), 3.85-3.92 (m, 1H), 3.95-4.07 (m, 2H), 6.21 (s a, 1H), 7.03-7.11 (m, 2H), 7.58-7.63 (m, 1H).

ESI-MS m/z 418 [M++H]

Ejemplo 71

Estructura química Nombre de compuesto: N-[3-((4aR*,5R*,8aS*)-2-amino-5-metil-4,4a,5,6,8,8ahexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil-4-metil[1,2,3]tiadiazol-5-carboxamida

1H-RMN (400MHz, CDCl3) δ (ppm): 0.91 (d, J=6.4Hz, 3H), 2.07-2.20 (m, 1H), 2.44-2.52 (m, 1H), 2.78-2.86 (m, 1H), 2.86-2.93 (m, 1H), 2.96 (s, 3H), 3.223.31 (m, 1H), 3.66-3.74 (m, 1H), 3.84-3.91 (m, 1H), 4.02-4.08 (m, 1H), 7.057.12 (m, 1H), 7.14-7.19 (m, 1H), 7.91 (s a, 1H).

ESI-MS m/z 422 [M++H]

[Tabla 10-3]

Ejemplo 72

Estructura química Nombre de compuesto:N-[3-((4aR*,5R*,8aS*)-2-amino-5-metil-4,4a,5,6tetrahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]-3-piperidin-1ilpropionamida

1H-RMN(400MHz, CDCl3)δ(ppm):0.92(d,J=6 8Hz,3H), 1.56-1.86(m,6H),2.102.23(m, 1H), 2.42-2.73(m, 9H),2.84-2.96(m,2H),3.24-3.36( m,1H),3.834.01(m,2H),4.06-4.13(m,1H),6.9 6-7.12 (m,2H),7.90-8.01(m,1H), 11.5(s a,1H).

ESI-MS m/z 435[M++H]

Ejemplo 73

Estructura química Nombre de compuesto:N-[3-((4aR*,5R*,8aS*)-2-amino-5-metil-4,4a,5,6tetrahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]-2-metiloxazol-4carboxa mide

1H-RMN(400MHz, CDCl3)δ(ppm):0.91(d, J=6. 8Hz,3H),2.11-2.27(m, 1H),2,42-2.50(m, 1H),2.5 0-2.57(m,3H),2.80-2.94 (m,2H),3.23-3.34(m,1 H),3.72-3.81(m,1H),3.89-3.97(m,1H),4.05-4.1 2(m,1H),6.99-7.08(m,1H),7.257.32(m,1H),7.8 9-7.96(m,1H),8.14-8.19(m,1H),8.65(s a,1H).

ESI-MS m/z 405[M++H]

Ejemplo 74
Síntesis de (4aR,6R,8aS)-8a-[2-fluoro-5-(2H-pirazol-3-il)fenil]-6-metoximetil-4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1azanaftalen-2-il]amina
[Fórmula 60] imagen59
(1) Síntesis de [(4aR,6R,8aS)-8a-(5-bromo-2-fluorofenil)-6-metoximetil-4,4a,5,6,8,8a-hexahidropirano[3,4d][1,3]tiazin-2-il]imidodicarbonato de di-terc-butilo
El compuesto del título se sintetizó a partir del compuesto obtenido en el Ejemplo 7-(4) de preparación según el Ejemplo 16 (1)-(3) de preparación.
ESI-MS; m/z 611 [M++Na].
(2) Síntesis de [(4aR,6R,8aS)-8a-(5-acetil-2-fluorofenil)-6-metoximetil-4,4a,5,6,8,8a-hexahidropirano[3,4-d][1,3]tiazin2-il]imidodicarbonato de di-terc-butilo
El compuesto obtenido en el Ejemplo 74-(1) (2,73 g) se disolvió en 1,4-dioxano (40 ml), se añadieron secuencialmente 1-etoxiviniltri-n-butilestaño (2,42 ml), fluoruro de cesio (1,55 g) y bis(tri-t-butilfosfina)paladio (118 mg) a la disolución, y la mezcla se agitó en una atmósfera de nitrógeno a 100ºC. Después de 1,5 horas, la disolución de la reacción se dejó enfriar. La mezcla de reacción se filtró a través de celita y se lavó con acetato de etilo. El filtrado se concentró a presión reducida. Se añadieron acetato de etilo y KHSO4 1 N al residuo, y la capa orgánica se separó. La capa orgánica se lavó secuencialmente con KHSO4 1 N, con una disolución de bicarbonato de sodio y con salmuera. La capa orgánica se secó sobre sulfato de magnesio anhidro. El agente secante se eliminó mediante filtración, y el filtrado se concentró a presión reducida. El residuo se sometió a cromatografía en gel de sílice para obtener {(4aR,6R,8aS)-8a-[5-(1-etoxivinil)-2-fluorofenil]-6-metoximetil-4,4a,5,6,8,8a-hexahidropirano[3,4-d][1,3]tiazin2-il}imidodicarbonato de di-terc-butilo (1,91 g). Se disolvieron 1,5 g de 1,91 g del compuesto resultante en THF (10 ml). Después, se añadió ácido clorhídrico 2 N (3,5 ml), y la mezcla se agitó a temperatura ambiente. Después de una hora, se añadió acetato de etilo a la disolución de la reacción, y la mezcla se lavó secuencialmente con una disolución de bicarbonato de sodio y con salmuera. La capa orgánica se secó sobre sulfato de magnesio anhidro. El agente secante se eliminó mediante filtración, y el filtrado se concentró a presión reducida. El residuo se sometió a cromatografía en gel de sílice para obtener el compuesto del título (1,2 g).
ESI-MS; m/z 575 [M++Na].
(3) Síntesis de {(4aR,6R,8aS)-8a-[2-fluoro-5-(2H-pirazol-3-il)fenil]-6-metoximetil-4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia1-azanaftalen-2-il}carbamato.
El compuesto obtenido en el Ejemplo 74-(2) (207 mg) se disolvió en acetal dimetílico de N,N-dimetilformamida (2,3 ml), y después la disolución se agitó en una atmósfera de nitrógeno a 110ºC. Después de alrededor de 14 horas, la disolución de la reacción se dejó enfriar y después se concentró a presión reducida. Se añadió etanol (3 ml) al residuo, y se añadió después hidrato de hidrazina (78 l), seguido de agitación a temperatura ambiente. Después de alrededor de tres días, la disolución de la reacción se concentró a presión reducida. Se añadieron acetato de etilo y una disolución de bicarbonato de sodio al residuo, y la capa orgánica se separó. La capa orgánica se secó sobre sulfato de magnesio anhidro. El agente secante se eliminó mediante filtración, y el filtrado se concentró a presión reducida. El residuo se sometió a cromatografía en gel de sílice para obtener el compuesto del título (38 mg).
ESI-MS; m/z 477 [M++1].
(4) Síntesis de (4aR,6R,8aS)-8a-[2-fluoro-5-(2H-pirazol-3-il)fenil]-6-metoximetil-4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia1-azanaftalen-2-il]amina
El compuesto obtenido en el Ejemplo 74-(3) (38 mg) se disolvió en diclorometano (2 ml), y se añadió después ácido trifluoroacético (0,4 ml), seguido de agitación a temperatura ambiente. Después de tres horas, la disolución de la reacción se concentró a presión reducida. Se añadieron cloroformo y una disolución de bicarbonato de sodio al residuo, y la capa orgánica se separó. La capa orgánica se secó sobre sulfato de magnesio anhidro. El agente secante se eliminó mediante filtración, y el filtrado se concentró a presión reducida. El residuo se sometió a cromatografía en columna para obtener el compuesto del título (18 mg).
ESI-MS; m/z 377 [M++1]
Ejemplo 75
Síntesis de (4aR,6R,8aS)-8a-[2-fluoro-5-(2H-pirazol-3-il)fenil]-6-metoximetil-4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1azanaftalen-2-il]amina imagen60
10 El compuesto del título se sintetizó según el Ejemplo 74 usando acetal dimetílico de N,N-dimetilacetamida en lugar de acetal dimetílico de N,N-dimetilformamida.
ESI-MS; m/z 391 [M++1].
Ejemplo 76
Síntesis de (4aR,6R,8aS)-8a-[2-fluoro-5-(2-fluoropiridin-3-il)fenil]-6-metoximetil-4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia15 1-azanaftalen-2-il]amina imagen61
(1) Síntesis de [(4aR,6R,8aS)-8a-[2-fluoro-5-(2-fluoropiridin-3-il)fenil]-6-metoximetil-4,4a,5,6,8,8ahexahidropirano[3,4-d][1,3]tiazin-2-il]imidodicarbonato de di-terc-butilo
El compuesto obtenido en el Ejemplo 74-(1) (1,33 g) se disolvió en THF (28 ml). Se añadieron ácido 2-fluoropiridin-3
20 borónico (955 mg), fluoruro de potasio (558 mg), Pd2DBA3 (200 mg) y Pd(t-Bu3P)2 (220 mg) a la disolución, y la mezcla se agitó en una atmósfera de nitrógeno a temperatura ambiente toda la noche. La disolución de la reacción se diluyó con acetato de etilo y se filtró a través de gel de sílice NH. El filtrado se lavó adicionalmente con una mezcla de acetato de etilo:heptano = 4:1. El filtrado se concentró a presión reducida para obtener un residuo. El residuo se sometió a cromatografía en gel de sílice para obtener el compuesto del título (547 mg).
25 ESI-MS; m/z 628 [M++Na].
(2) Síntesis de (4aR,6R,8aS)-8a-[2-fluoro-5-(2-fluoropiridin-3-il)fenil]-6-metoximetil-4,4a,5,6,8,8a-hexahidro-7-oxa-3tia-1-azanaftalen-2-il]amina
El compuesto obtenido en el Ejemplo 76-(1) (67 mg) se disolvió en diclorometano (2 ml), y después se añadió TFA (0,5 ml). Después de dos horas, la disolución de la reacción se concentró a presión reducida. Se añadieron
30 cloroformo, una disolución 1 N de hidróxido de sodio y una disolución de bicarbonato de sodio al residuo, y la capa orgánica se separó. La capa orgánica se secó sobre sulfato de magnesio anhidro. El agente secante se eliminó mediante filtración, y el filtrado se concentró. El residuo se sometió a cromatografía en gel de sílice para obtener el compuesto del título (30 mg).
ESI-MS; m/z 406 [M++1].
Ejemplo 77
Síntesis de (4aR,6R,8aS)-8a-[2-fluoro-5-(3-fluoropiridin-4-il)fenil-6-metoximetil-4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1azanaftalen-2-il]amina imagen62
El compuesto del título se sintetizó según el Ejemplo 76. ESI-MS; m/z 406 [M++1].
Ejemplo 78
Síntesis de (4aR,6R,8aS)-8a-[2-fluoro-5-(2-metoxipiridin-3-il)fenil]-6-metoximetil-4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia10 1-azanaftalen-2-il]amina
[Fórmula 64] imagen63
(1) Síntesis de {(4aR,6R,8aS)-8a-[2-fluoro-5-(2-metoxipiridin-3-il)fenil]-6-metoximetil-4,4a,5,6,8,8a-hexahidro-7-oxa3-tia-1-azanaftalen-2-il}carbamato de t-butilo
15 Se añadieron metanol (1 ml) y una disolución de metóxido de sodio al 28%-metanol (1 ml) al compuesto sintetizado en el Ejemplo 76-(1) (164 mg), seguido de agitación a 50ºC. Después de tres horas y 30 minutos, la disolución de la reacción se dejó enfriar. Se añadieron acetato de etilo y una disolución saturada de cloruro de amonio a la disolución de la reacción, y la capa orgánica se separó. La capa orgánica se lavó con salmuera. La capa orgánica se secó sobre sulfato de magnesio anhidro. El agente secante se eliminó mediante filtración, y el filtrado se concentró a
20 presión reducida. El residuo se sometió a cromatografía en gel de sílice para obtener el compuesto del título (114 mg).
ESI-MS; m/z 540 [M++Na].
(2) Síntesis de {(4aR,6R,8aS)-8a-[2-fluoro-5-(2-metoxipiridin-3-il)fenil]-6-metoximetil-4,4a,5,6,8,8a-hexahidro-7-oxa3-tia-1-azanaftalen-2-il}amina
25 El compuesto obtenido en el Ejemplo 78-(1) (114 mg) se disolvió en diclorometano (3 ml), y después se añadió TFA (1 ml), seguido de agitación a temperatura ambiente. Después de tres horas, la disolución de la reacción se concentró a presión reducida. Se añadieron cloroformo y una disolución de bicarbonato de sodio al residuo, y la capa orgánica se separó. La capa orgánica se secó sobre sulfato de magnesio anhidro. El agente secante se eliminó mediante filtración, y el filtrado se concentró a presión reducida. El residuo se sometió a cromatografía en columna
30 para obtener el compuesto del título (61 mg).
ESI-MS; m/z 418 [M++1].
Ejemplo 79
Síntesis de (4aR,6R,8aS)-8a-[2-fluoro-5-piridazin-3-ilfenil]-6-metoximetil-4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1azanaftalen-2-il]amina imagen64
(1) Síntesis de [(4aR,6R,8aS)-8a-(2-fluoro-5-piridazin-3-ilfenil)-6-metoximetil-4,4a,5,6,8,8a-hexahidropirano[3,4d][1,3]tiazin-2-il]imidodicarbonato de di-terc-butilo
El compuesto sintetizado en el Ejemplo 76-(1) (229 mg) se disolvió en 1,4-dioxano (4 ml). Se añadieron
5 secuencialmente 3-(tributilestannil)piridazina (215 mg), fluoruro de cesio (130 mg) y bis(tri-t-butilfosfina)paladio (10 mg) a la disolución, y la mezcla se agitó en una atmósfera de nitrógeno a 100ºC. Después de dos horas, la disolución de la reacción se dejó enfriar. La mezcla de reacción se filtró a través de celita y se lavó con acetato de etilo. El filtrado se concentró a presión reducida. El residuo se sometió a cromatografía en gel de sílice para obtener el compuesto del título (116 mg).
10 ESI-MS; m/z 611 [M++Na].
(2) Síntesis de (4aR,6R,8aS)-8a-[2-fluoro-5-piridazin-3-ilfenil]-6-metoximetil-4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1azanaftalen-2-il]amina
El compuesto obtenido en el Ejemplo 79-(1) (116 mg) se disolvió en diclorometano (3 ml), y después se añadió TFA (1 ml), seguido de agitación a temperatura ambiente. Después de tres horas, la disolución de la reacción se
15 concentró a presión reducida. Se añadieron cloroformo y una disolución de bicarbonato de sodio al residuo, y la capa orgánica se separó. La capa orgánica se secó sobre sulfato de magnesio anhidro. El agente secante se eliminó mediante filtración, y el filtrado se concentró a presión reducida. El residuo se sometió a cromatografía en columna para obtener el compuesto del título (48 mg).
ESI-MS; m/z 389 [M++1].
20 Ejemplo 80
El siguiente compuesto, como se muestra en la siguiente Tabla 11, se sintetizó según el Ejemplo 2 usando los ácidos carboxílicos correspondientes.
[Tabla 11]

Ejemplo 80

Nombre de compuesto: N-[3-((4aR*,6R*,8aS*)-2-amino-6-trifluorometil4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-aza-naftalen-8a-il)-4-fluorofenil]-5difluorometilpiridin-2-carboxamida

ESI-MS m/z 505 [M++H]

25 Ejemplo 81
Síntesis de N-[3-((4aR*,8aS*)-2-amino-4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]-5etoxipirazin-2-carboxamida imagen65
(1) Síntesis de ácido 5-etoxipirazin-2-carboxílico
Una disolución 5 N de hidróxido de sodio (2 ml) se añadió a una disolución de 5-cloropirazin-2-carboxilato de metilo (150 mg) en etanol (4 ml), y la mezcla se agitó a temperatura ambiente durante cinco horas. Se añadieron acetato de etilo y agua a la disolución de la reacción, y la capa acuosa se separó. La capa acuosa se hizo ácida con ácido
5 clorhídrico concentrado. Se añadieron salmuera y acetato de etilo a la mezcla, y la capa orgánica se separó. La capa orgánica se secó sobre sulfato de magnesio anhidro. La capa orgánica se concentró para obtener el compuesto del título (135 mg).
1H-RMN (400 MHz, CDCl3) δ (ppm): 1,46 (t, J = 7,2 Hz, 3H), 4,51 (q, J = 7,2 Hz, 2H), 8,17 (s, 1H), 8,96 (s, 1H).
(2) Síntesis de N-[3-((4aR*,8aS*)-2-amino-4,4a,5,6,8,8a-hexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]-510 etoxipirazin-2-carboxamida
El compuesto del título (30 mg) se obtuvo a partir del compuesto obtenido en el Ejemplo 1-(9) de preparación (30 mg), y el compuesto obtenido en el Ejemplo 81-(1) (16,9 mg) según el Ejemplo (2).
ESI-MS; m/z 432 [M++H]
1H-RMN (400 MHz, CDCl3) δ (ppm): 1,40-1,46 (m, 1H), 1,45 (t, J = 7,2 Hz, 3H), 2,07-2,18 (m, 1H), 2,64 (dd, J = 2,8,
15 8,0 Hz, 1H), 2,94 (ddd, J = 4,0, 7,6, 11,6 Hz, 1H), 3,02 (dd, J = 4,0, 12,0 Hz, 1H), 3,65-3,71 (m, 1H), 3,78 (d, J = 10,8 Hz, 1H), 4,04-4,11 (m, 2H), 4,49 (q, J = 7,2 Hz, 2H), 7,06 (dd, J = 8,8, 12,0 Hz, 1H), 7,32 (dd, J = 2,8, 7,2 Hz, 1H), 7,99-8,03 (m, 1H), 8,11 (s, 1H), 8,98 (s, 1H), 9,47 (s, 1H).
Ejemplos 82 a 87
Los compuestos de los Ejemplos 82 a 87 se sintetizaron según el Ejemplo 3 usando los ácidos carboxílicos 20 correspondientes, como se muestra en la siguiente Tabla 12.
[Tabla 12-1] [Tabla 12-2]

Ejemplo 82

Estructura química Nombre de compuesto: N-[3-((8S*,8aR*)-2-amino-4,4a,5,6,8,8ahexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]-5-metoxipirazin-2carboxamida

1H-RMN (400MHz, CDCl3): δ (ppm):1.44-1.47 (m,1H), 2.08-2.18 (m, 1H), 2.64 (dd, J = 2.4, 12.0 Hz, 1H), 2.89-2.98 (m, 1H), 3.03 (dd, J = 4.0, 12.0 Hz, 1H), 3.65-3.72 (m, 1H), 3.79 (d, J = 10.8 Hz, 1H), 4.02-4.12 (m, 5H), 7.07 (dd, J = 8.8, 12.0 Hz, 1H), 7.32 (dd, J = 2.8, 6.8 Hz, 1H), 8.02 (ddd, J = 2.8, 4.0, 8.8 Hz, 1H), 8.15 (d, J = 1.2 Hz, 1H), 9.01 (d, J = 1.6 Hz, 1H), 9.48 (s a, 1H)

ESI-MS m/z 418 [M++H]

Ejemplo 83

Estructura química Nombre de compuesto: N-[3-((8S*,8aR*)-2-amino-4,4a,5,6,8,8ahexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]-5-metoxipiridin-2carboxamida

1H-RMN (400 MHz, CDCl3): 1.42-1.47 (m, 1H), 2.08-2.20 (m, 1H), 2.63 (dd, J = 2.8, 12.4 Hz, 1H), 2.91-2.97 (m, 1H), 3.03 (dd, J = 4.0, 12.4 Hz, 1H), 3.65-3.72 (m, 1H), 3.78 (d, J = 10.8 Hz, 1H), 3.94 (s, 3H), 4.05-4.11 (m, 2H), 7.06 (dd, J = 8.8, 12.0 Hz, 1H) 7.33 (dd, J = 2.8, 8.8 Hz, 2H), 8.04 (ddd, J = 2.8, 4.0, 8.8 Hz, 1H), 8.23 (d, J = 8.8 Hz, 1H), 8.27 (d, J = 2.8 Hz, 1H) 9.80 (s a, 1H)

ESI-MS m/z 417 [M++H]

Ejemplo 84

Estructura química Nombre de compuesto: N-[3-((8S*,8aR*)-2-amino-4,4a,5,6,8,8ahexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]-5fluorometoxipiridin-2-carboxamida

1H-RMN (400 MHz, CDCl3): 1.44-1.48 (m, 1H), 2.09-2.19 (m, 1H), 2.65 (dd, J = 3.2, 12.4 Hz, 1H), 2.95-2.99 (m, 1H), 3.04 (dd, J = 4.0, 12.0 Hz, 1H), 3.65-3.72 (m, 1H), 3.80 (d, J = 11.2 Hz, 1H), 4.04-4.13 (m, 2H), 5.81 (d, J = 50.0 Hz, 2H), 7.08 (dd, J = 8.8, 12.0 Hz, 1H) 7.35 (dd, J = 2.8, 6.8 Hz, 1H), 7.57 (ddd, J = 0.8, 2.8, 8.4 Hz, 1H), 8.05 (ddd, J = 2.8, 4.4, 8.8 Hz, 1H), 8.28 (dd, J = 0.4, 8.4 Hz, 1H), 8.42 (d, J = 2.8 Hz, 1H), 9.82 (s a, 1H)

ESI-MS m/z 435 [M++H]

Ejemplo 85

Estructura química Nombre de compuesto: N-[3-((8S*,8aR*)-2-amino-4,4a,5,6,8,8ahexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]-3-cloro-5trifluorometilpiridin-2-carboxamida

1H-RMN (400 MHz, CDCl3): 1.45-1.48 (m, 1H), 2.07-2.18 (m, 1H), 2.66 (dd, J = 2.8, 12.4 Hz, 1H), 2.95-3.05 (m, 2H), 3.65-3.72 (m, 1H), 3.78 (d, J = 11.2 Hz, 1H), 4.03-4.12 (m, 2H), 7.07-7.12 (m, 1H), 7.21 (dd, J = 2.4, 6.8 Hz, 1H), 8.13-8.18 (m, 2H), 8.79 (dd, J = 0.8, 4.0 Hz, 1H), 9.75 (s a, 1H)

ESI-MS m/z 489 [M++H]

[Tabla 12-3]

Ejemplo 86

Estructura química Nombre de compuesto: N-[3-((8S*,8aR*)-2-amino-4,4a,5,6,8,8ahexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]-5-metilpiridin-2carboxamida

1H-RMN (400 MHz, CDCl3): 1.44-1.47 (m, 1H), 2.12-2.15 (m, 1H), 2.65 (dd, J = 2.8, 12.4 Hz, 1H), 2.70 (s, 3H), 2.93-2.97 (m, 1H), 3.03 (dd, J = 4.0, 12.4 Hz, 1H), 3.66-3.72 (m, 1H), 3.78 (d, J = 11.2 Hz, 1H), 4.05-4.12 (m, 2H), 7.08 (dd, J = 8.8, 12.0 Hz, 1H) 7.36 (dd, J = 2.8, 6.8 Hz, 1H), 8.01-8.05 (m, 1H) 8.44 (s, 1H), 9.36 (d, J = 0.8 Hz, 1H), 9.61 (s a, 1 H)

ESI-MS m/z 402 [M++H]

Ejemplo 87

Estructura química Nombre de compuesto: N-[3-((8S*,8aR*)-2-amino-4,4a,5,6,8,8ahexahidro-7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]-2-metiloxazol-4carboxamida

1H-RMN (400 MHz, CDCl3): 1.45-1.48 (m, 1H), 2.11-2.14 (m, 1H), 2.53 (s, 3H), 2.63-2.67 (m, 1H), 2.95-3.05 (m, 2H), 3.65-3.71 (m, 1H), 3.81 (d, J = 11.6 Hz, 1H), 4.03-4.06 (m, 1H), 4.08-4.12 (m, 1H), 7.03-7.09 (m, 1H), 7.30-7.32 (m, 1H), 7.93-7.97 (m, 1H), 8.17 (s, 1H), 8.71 (s a, 1H)

ESI-MS m/z 391 [M++H]

Ejemplo 88
El compuesto del Ejemplo 88 se sintetizó según el Ejemplo 2 usando el ácido carboxílico correspondiente y el intermedio anilínico correspondiente en los Ejemplos de Preparación, como se muestra en la siguiente Tabla 13.
[Tabla 13]

Ejemplo 88

Estructura química Nombre de compuesto: N-[3-((8S,8aS)-2-amino-5-fluoro-4,4a,5,6-tetrahidro7-oxa-3-tia-1-azanaftalen-8a-il)-4-fluorofenil]-5-metoxipirazin-2-carboxamida

1H-RMN (400 MHz, CDCl3): 2.87-2.91 (m, 1H), 3.01-3.06 (m, 1H), 3.16 (dd, J = 2.8, 12.4 Hz, 1H), 3.53 (dt, J = 4.8, 10.4 Hz, 1H), 3.75 (dd, J = 2.0, 10.8 Hz, 1H), 4.07-4.10 (m, 4H), 4.26 (dd, J = 1.6, 10.8 Hz, 1H), 4.84-4.98 (m, 1H), 7.10 (dd, J = 8.8, 12.0 Hz, 1H), 7.36 (dd, J = 2.4, 6.8 Hz, 1H), 7.97-8.01 (m, 1H), 8.15 (d, J = 1.2 Hz, 1H), 9.01 (d, J = 1.2 Hz, 1H), 9.48 (s a, 1H)

ESI-MS m/z 436 [M++H]

Ejemplo 1 de Ensayo
Cuantificación del péptido A en cultivo de neuronas de cerebro de feto de rata
5 (1) Cultivo neuronal primario de rata
Se prepararon cultivos neuronales primarios a partir de la corteza cerebral de ratas embriónicas de 18 días Wistar (Charles River Japan, Yokohama, Japón). Específicamente, los embriones se retiraron asépticamente de ratas preñadas bajo anestesia con éter. El cerebro se aisló del embrión y se sumergió en medio L-15 enfriado con hielo (tal como número de Catálogo 11415-064 de Invitrogen Corp., Carlsbad, CA, USA, o SIGMAL1518). La corteza 10 cerebral se recogió del cerebro aislado bajo microscopio estereoscópico. Los fragmentos de corteza cerebral recogidos se trataron enzimáticamente en una disolución de enzima que contiene 0,25% de tripsina (número de Catálogo 15050-065 de Invitrogen Corp., Carlsbad, CA, USA) y 0,01% de DNase (Sigma D5025, St. Louis, MO, USA) a 37ºC durante 30 minutos, para dispersar las células. Aquí, la reacción enzimática se detuvo añadiendo a la disolución suero de caballo inactivado. La disolución tratada enzimáticamente se centrifugó a 1.500 rpm durante 15 cinco minutos para eliminar el sobrenadante. A la masa celular resultante se añadieron 5 a 10 ml de un medio. Como el medio (Neurobasal/B27/2-ME), se usó medio Neurobasal (número de Catálogo de Invitrogen Corp. 21103049, Carlsbad, CA, USA) suplementado con 2% de suplemento B27 (número de Catálogo de Invitrogen Corp. 17504-044, Carlsbad, CA, USA), 25 M de 2-mercaptoetanol (2-ME, número de Catálogo de WAKO 139-06861, Osaka, Japón) 0,5 mM de L-glutamina (número de Catálogo de Invitrogen Corp. 25030-081, Carlsbad, CA, USA), y 20 antibióticos-antimicóticos (número de Catálogo de Invitrogen Corp. 15240-062, Carlsbad, CA, USA). Sin embargo, para el ensayo, se usó el medio Neurobasal anterior no suplementado con 2-ME (Neurobasal/B27). Las células se volvieron a dispersar pipeteando levemente la masa celular a la que se añadió el medio. La dispersión celular se filtró a través de una malla de nailon de 40 m (Cell Strainer, número de Catálogo 35-2340, Becton Dickinson Labware, Franklin Lakes, NJ, USA) para eliminar la masa celular que queda, y de este modo se obtuvo una
25 suspensión de células neuronales.
La suspensión de células neuronales se diluyó con el medio y después se colocó en placas en un volumen de 100 l/pocillo a una densidad celular inicial de 5 X 105 células/cm2 en una placa de cultivo de poliestireno de 96 pocillos previamente revestida con poli-L o D-lisina (número de Catálogo de Falcon 35-3075, Becton Dickinson Labware, Franklin Lakes, NJ, USA revestido con poli-L-lisina usando el método mostrado más abajo, o placa de 96 pocillos de 30 utensilio para células con poli-D-lisina en entornos celulares BIOCOAT™, número de Catálogo 35-6461, Becton Dickinson Labware, Franklin Lakes, NJ, USA). El revestimiento con poli-L-lisina se llevó a cabo según lo siguiente. Se prepararon asépticamente 100 g/ml de una disolución de poli-L-lisina (SIGMA P2636, St. Louis, MO, USA) con un tampón de borato 0,15 M (pH 8,5). A la placa de cultivo de poliestireno de 96 pocillos se añadieron 100 g/pocillo de la disolución y se incubó a temperatura ambiente durante una o más horas, o a 4ºC toda la noche o más.
35 Después, la placa de cultivo de poliestireno de 96 pocillos revestida se lavó con agua estéril cuatro o más veces, y después se secó o aclaró con, por ejemplo, PBS o medio estéril, y se usó para la colocación de las células en la placa. Las células colocadas en placas se cultivaron en la placa de cultivo a 37ºC en 5% de CO2-95% de aire durante un día. Después, la cantidad total del medio se sustituyó por medio Neurobasal/B27/2-ME reciente, y después las células se cultivaron durante otros tres días.
40 (2) Adición de compuesto
El fármaco se añadió a la placa de cultivo en el Día 4 de cultivo como sigue. La cantidad total del medio se eliminó de los pocillos, y se le añadieron 180 l/pocillo de medio Neurobasal que no contiene 2-ME y que contiene 2% de B27 (Neurobasal/B27). Una disolución del compuesto de ensayo en dimetilsulfóxido (en lo sucesivo abreviado DMSO) se diluyó con Neurobasal/B27 hasta una concentración 10 veces mayor que la concentración final. Se añadieron 20
45 l/pocillo de la dilución a y se mezclaron suficientemente con el medio. La concentración final de DMSO fue 1% o menos. Al grupo de control sólo se añadió DMSO.

(3)

Toma de muestras

Las células se cultivaron durante tres días tras la adición del compuesto, y se recogió la cantidad total del medio. El medio resultante se usó como una muestra de ELISA. La muestra no se diluyó para la medida de ELISA de Ax-42 y se diluyó hasta 5 veces con un diluyente suministrado con un kit de ELISA para la medida de ELISA de Ax-40.

(4)

Evaluación de la supervivencia celular

5 La supervivencia celular se evaluó mediante un ensayo de MTT según el siguiente procedimiento. Después de recoger el medio, se añadieron a los pocillos 100 l/pocillo de un medio previamente calentado. Además, se añadieron a los pocillos 8 l/pocillo de una disolución de 8 mg/ml de MTT (SIGMA M2128, St. Louis, MO, USA) en D-PBS(-) (disolución salina tamponada con fosfato de Dulbecco, SIGMA D8537, St. Louis, MO, USA). La placa de cultivo de poliestireno de 96 pocillos se incubó en una incubadora a 37ºC en 5% de CO2-95% de aire durante 20
10 minutos. Se le añadieron 100 l/pocillo de un tampón de lisis de MTT, y los cristales de MTT formazano se disolvieron suficientemente en el tampón en la incubadora a 37ºC en 5% de CO2-95% de aire. Después, se midió la absorbancia a 550 nm en cada pocillo. El tampón de lisis de MTT se preparó según lo siguiente. Se disolvieron 100 g de SDS (dodecilsulfato de sodio (laurilsulfato de sodio), WAKO 191-07145, Osaka, Japón) en una disolución mixta de 250 ml de N,N-dimetilformamida (WAKO 045-02916, Osaka, Japón) con 250 ml de agua destilada. Se añadieron
15 adicionalmente a la disolución 350 l de cada uno de ácido clorhídrico concentrado y ácido acético, para permitir que la disolución tenga un pH final de alrededor de 4,7.
Con la medida, los pocillos que no tienen células en las placas y que sólo contienen el medio y disolución de MTT se establecieron como fondo (bkg). Los valores medidos se aplicaron respectivamente a la siguiente fórmula, que incluye la resta de los valores bkg de ellos. De este modo, la proporción frente al grupo de control (grupo no tratado
20 con el fármaco, CTRL) (% de CTRL) se calculó para comparar y evaluar las actividades de supervivencia celular.
% de CTRL = (A550_muestra -A550_bkg)/(A550_CTRL – A550_bkg) x 100
(A550_muestra: absorbancia a 550 nm del pocillo de muestra, A550_bkg: absorbancia a 550 nm de pocillo de fondo, A550_CTRL: absorbancia a 550 nm de pocillo del grupo de control)
(5) ELISA de A
25 Para ELISA de A, se usó kit de ELISA de  amiloide (42) humana/rata Wako (#290-62601) y kit de ELISA de  amiloide (40) humana/rata Wako (#294-62501) de Wako Pure Chemical Industries, Ltd. El ELISA de A se llevó a cabo según los protocolos recomendados por los fabricantes (métodos descritos en los documentos adjuntos). Sin embargo, la curva de calibración de A se creó usando el péptido beta-amiloide 1-42 de rata y el péptido betaamiloide 1-40 de rata (Calbiochem, #171596 [A42], #171593 [A40]). Los resultados se muestran en la Tabla 14 en
30 términos del valor de IC50 (M) para disminuir la concentración de A42 en el medio.
[Tabla 14]

Compuesto ensayo

de IC50 del efecto reductor producción de A42 (M) de la Compuesto ensayo de IC50 del efecto reductor de la producción de A42 (M)

1

imagen66 0.0017 imagen67 33 imagen68 0.0011

2

imagen69 0.002 imagen70 34 imagen71 0.002

3

imagen72 0.001 imagen73 35 imagen74 0.0021

4

imagen75 0.011 imagen76 36 imagen77 0.0005

5

imagen78 0.058 imagen79 37 imagen80 0.002

6

imagen81 0.0012 imagen82 38 imagen83 0.003

7

imagen84 0.0007 imagen85 39 imagen86 0.001

8

imagen87 0.0016 imagen88 40 imagen89 0.002

9

imagen90 0.0006 imagen91 41 imagen92 0.002

Compuesto ensayo

de IC50 del efecto reductor producción de A42 (M) de la Compuesto de ensayo IC50 del efecto reductor de la producción de A42 (M)

10

imagen93 0.001 imagen94 42 0.0009

11

imagen95 0.0007 imagen96 43 0.0017

12

imagen97 0.0011 imagen98 44 0.0007

13

imagen99 0.001 imagen100 45 0.002

14

imagen101 0.0008 imagen102 46 0.001

15

imagen103 0.0004 imagen104 47 0.004

16

imagen105 0.0011 imagen106 48 0.002

17

imagen107 0.004 imagen108 49 0.002

18

imagen109 0.007 imagen110 50 0.002

19

imagen111 0.002 imagen112 51 0.006

20

imagen113 0.009 imagen114 52 0.002

21

imagen115 0.01 imagen116 53 0.0056

22

imagen117 0.004 imagen118 54 0.002

23

imagen119 0.012 imagen120 55 0.0014

24

imagen121 0.009 imagen122 56 0.003

25

imagen123 0.014 imagen124 57 0.002

26

imagen125 0.003 imagen126 58 0.004

27

imagen127 0.008 imagen128 59 0.087

28

imagen129 0.0014 imagen130 60 0.032

29

imagen131 0.003 imagen132 61 0.319

30

imagen133 0.006 imagen134 64 0.014

31

imagen135 0.0019 imagen136 65 0.37

32

imagen137 0.003 imagen138 66 0.263

Como está claro a partir de los resultados de la Tabla 14, se demostró que el compuesto de la presente invención tiene un efecto reductor de la producción de A42. Aplicabilidad industrial El compuesto de la fórmula general (I) o su sal farmacéuticamente aceptable, o solvato del mismo, según la
presente invención tiene un efecto reductor de la producción de A42. De este modo, la presente invención puede proporcionar particularmente un agente profiláctico o terapéutico para una enfermedad neurodegenerativa provocada por A, tal como demencia de tipo Alzheimer o síndrome de Down.
1H-NMR (400 MHz, CDCl3) δ (ppm): 1.15 (d, J = 5.6 Hz, 3H), 1.22 (t, J = 6.8 Hz, 6H), 2.13- 2.23 (m, 1H), 2.28-2.38 (m, 1H), 3.43-3.64 (m, 5H), 3.66-3.76 (m, 2H), 4, 59 (t, J = 5.2 Hz, 1H), 5.01-5.10 (m, 2H), 5.76-5.88 (m, 1H).
(2) Synthesis of oxime of (1-methyl-3-butenyloxy) acetaldehyde
The compound obtained in the previous step (5.81 g) was dissolved in a mixed solution of formic acid (30 ml) and water (10 ml) at room temperature, followed by stirring for six hours. Hydroxylamine sulfate (4.42 g) and sodium acetate (4.41 g) were added to the reaction solution, and the mixture was stirred at room temperature for 14 hours. Saturated aqueous sodium chloride was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (2.95 g).
1H-NMR (400 MHz, CDCl3) δ (ppm): 1.17 (d, J = 6.0 Hz, 3H), 2.15-2.25 (m, 1H), 2.28-2.39 (m, 1H), 3.47-3.60 (m, 1H), 4.05-4.18 (m, 1H), 4.30-4.44 (m, 1H), 5.04-5 , 14 (m, 2H), 5.74-5.88 (m, 1H), 7.45-7.52 (m, 2H).
In Example 6- (3), (4) and (5) of preparation, the synthesis was carried out according to Example 1- (2), (3) and (4) of preparation.
In Example 6- (6), (7) and (8) of preparation, the synthesis was carried out according to Example 5- (3), (4) and (5) of preparation.
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In Example 6- (9), (10) and (11) of preparation, the synthesis was carried out according to Example 1- (7) and (8) of preparation.
(12) Synthesis of (-) - [(4aR *, 6S *, 8aS *) - 8a- (5-amino-2-fluorophenyl) -6-methyl-4,4a, 5,6,8,8a-hexahydro Tert-butyl-7-oxa-3-thia-1-appleftalen-2-yl] carbamate
The compound obtained in the previous stage (27 mg) was purified by CHIRALPAK ™ AD-H (mobile phase: hexane: ethanol = 7: 3, flow rate: 10 ml / min.), And the fraction with a retention time of 16 to 19 minutes was collected to obtain the title compound. This operation was repeated to obtain the title compound (228 mg;> 99% ee) from 540 mg of the racemate.
1H-NMR (400 MHz, CDCl3) δ (ppm): 1.28 (d, J = 6.0 Hz, 3H), 1.53 (s, 9H), 1.55-1.61 (m, 1H ), 1.80-1.93 (m, 1H),
10 2.47-2.55 (m, 1H), 2.93-3.01 (m, 1H), 3.02-3.11 (m, 1H), 3.59-3.82 (m, 4H), 4.11-4.18 (m, 1H), 6.54-6.62 (m, 2H), 6.81-6.89 (m, 1H).
Preparation Example 7
Synthesis of (-) - [(4aR *, 6R *, 8aS *) - 8a- (5-amino-2-fluorophenyl) -6-methoxymethyl-4,4a, 5,6,8,8a-hexahydro-7- tert-butyl oxa-3-thia-1azanaftalen-2-yl] carbamate
15 [Formula 32] image29
(1) Synthesis of (R) -1-methoxy-4-penten-2-ol
Copper iodide (630 mg) was suspended in tetrahydrofuran (200 ml), and a 1.38 M solution of vinyl magnesium chloride in tetrahydrofuran (32.3 ml) was added at -78 ° C, followed by stirring for 10 minutes. (R) - (20) Glycidyl methyl ether (2 ml) was added to the reaction solution at the same temperature, and the mixture was stirred at -78 ° C for two hours and 25 minutes and at 0 ° C for 25 minutes. A saturated solution of ammonium chloride was added to the reaction solution. The mixture was extracted sequentially with a mixed solution of hexane and ethyl acetate (1: 1), ethyl acetate and diethyl ether. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure to obtain the title compound.
25 (2.60 g).
1H-NMR (400 MHz, CDCl3) δ (ppm): 2.21-2.30 (m, 3H), 3.29 (dd, J = 9.6, 7.7 Hz, 1H), 3.39 (s, 3H), 3.43 (dd, J = 9.6, 3.1 Hz, 1H), 3.81-3.90 (m, 1H), 5.09-5.18 (m, 2H ), 5.78-5.91 (m, 1 H).
In Example 7- (2) and (3) of preparation, the synthesis was carried out according to Example 6- (1) and (2) of preparation.
In Example 7- (4), (5) and (6) of preparation, the synthesis was carried out according to Example 1- (2), (3) and (4) of preparation.
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In Example 7- (7), (8) and (9) of preparation, the synthesis was carried out according to Example 5- (3), (4) and (5) of preparation.
In Example 7- (10), (11) and (12) of preparation, the synthesis was carried out according to Example 1- (7) and (8) of preparation.
5 (12) Synthesis of (-) - [(4aR *, 6R *, 8aS *) - 8a- (5-amino-2-fluorophenyl) -6-methoxymethyl-4,4a, 5,6,8,8a- tert-butyl hexahydro-7-oxa-3-thia-1azanaftalen-2-yl] carbamate
1H-NMR (400 MHz, CDCl3) δ (ppm): 1.48-1.57 (m, 1H), 1.53 (s, 9H), 1.82-1.96 (m, 1H), 2 , 49-2.56 (m, 1H), 2.96-3.03 (m, 1H), 3.04-3.13 (m, 1H), 3.37-3.43 (m, 1H) , 3.41 (s, 3H), 3.50-3.58 (m, 1H), 3.65 (sa, 2H), 3.70-3.77 (m, 1H), 3.82-3 , 91 (m, 1H) 4.13-4.20 (m, 1H), 6.54-6.61 (m, 2H), 6.82-6.89 (m, 1H).
10 Preparation Example 8
Synthesis of [(4aS, 5S, 8aS) -8a- (5-amino-2-fluorophenyl) -5-fluoro-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-2il] tert-butyl carbamate
[Formula 33] image30
15 (1) Synthesis of (R) -1- (tert-butyldimethylsilyloxy) -3-buten-2-ol
N-Butyllithium (58.2 ml, 2.64 M solution in hexane) was added dropwise to a suspension of trimethylsulfonium iodide (32.4 g) in tetrahydrofuran (400 ml) under a nitrogen atmosphere at - 20 ° C The reaction solution was stirred at the same temperature for 30 minutes. Tert-Butyldimethylsilyl ether (R) - (-) - glycidyl (10 g) was added dropwise to the reaction solution at the same temperature. The reaction solution was stirred.
20 for three hours with gradual heating to room temperature. Aqueous ammonium chloride and ethyl acetate were added to the reaction solution, and the organic layer was separated. The organic layer was washed with saturated aqueous sodium chloride twice. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (9.6 g).
5
10
fifteen
twenty
25
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Four. Five
fifty
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1H-NMR (400 MHz, CDCl3) δ (ppm): 0.08 (s, 6H), 0.91 (s, 9H), 2.56 (d, J = 3.6 Hz, 1H), 3, 45 (dd, J = 7.6, 10.0 Hz, 1H), 3.66 (dd, J = 4.0, 10.0 Hz, 1H), 4.14-4.20 (m, 1H) , 5.19 (ddd, J = 1.6, 1.6, 10.8 Hz, 1H), 5.35 (ddd, J = 1.6, 1.6, 17.6 Hz, 1H), 5 , 81 (ddd, J = 6.0, 10.4, 17.6 Hz, 1H).
(2) Synthesis of tert-butyl - ((R) -2-methoxymethoxy-3-butenyloxy) dimethylsilane
Chloromethyl methyl ether (9.03 ml) was added dropwise to a solution of the compound obtained in Example 8- (1) of preparation (9.6 g) and N, N-diisopropylethylamine (41.4 ml) in dichloromethane (200 ml) under ice cooling. The reaction solution was heated to room temperature, and stirred for 14 hours. Saturated aqueous sodium chloride was added to the reaction solution, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (11.3 g).
1H-NMR (400 MHz, CDCl3) δ (ppm): 0.07 (s, 6H), 0.89 (s, 9H), 3.39 (s, 3H), 3.60-3.70 (m , 2H), 4.09-4.14 (m, 1H), 4.64-4.72 (m, 2H), 5.27 (ddd, J = 1.2, 2.0, 10.8 Hz , 1H), 5.30 (ddd, J = 1.2, 2.0, 17.2 Hz, 1H), 5.74 (ddd, J = 6.8, 10.4, 17.6 Hz, 1H ).
(3) Synthesis of (R) -2-methoxymethoxy-3-buten-1-ol
Tetrabutylammonium fluoride (55 ml, 1 M solution in tetrahydrofuran) was added dropwise to a solution of the compound obtained in Example 8- (2) of preparation (11.3 g) in tetrahydrofuran (220 ml), and the mixture It was stirred at room temperature for two hours. Saturated aqueous sodium chloride and ethyl acetate were added to the reaction solution, and the organic layer was separated. Ethyl acetate was added to the aqueous layer, and the organic layer was separated again. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (4.15 g).
1H-NMR (400 MHz, CDCl3) δ (ppm): 2.37-2.41 (m, 1H), 3.42 (s, 3H), 3.58-3.64 (m, 2H), 4 , 11-4.15 (m, 1H), 4,654.4.75 (m, 2H), 5.27-5.34 (m, 2H), 5.75 (ddd, J = 6.4, 10, 0. 17.2 Hz, 1H).
(4) Synthesis of ((R) -2-methoxymethoxy-3-butenyloxy) ethyl acetate
Sodium hydride (2.5 g) was added to a solution of the compound obtained in Example 8- (3) of preparation (4.15 g) in 1-methyl-2-pyrrolidinone (60 ml) under ice cooling. The reaction solution was stirred at the same temperature for 30 minutes. Ethyl bromoacetate (10.4 ml) was added dropwise to the reaction solution. The reaction solution was heated to room temperature and stirred at the same temperature for five hours. Saturated aqueous ammonium chloride and ethyl acetate were added to the reaction solution, and the organic layer was separated. The organic layer was washed with aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (4.77 g).
1H-NMR (400 MHz, CDCl3) δ (ppm): 1.24-1.31 (m, 3H), 3.39 (s, 3H), 3.59-3.69 (m, 2H), 4 , 10-4.22 (m, 4H), 4.23-4.32 (m, 1H), 4.64-4.74 (m, 2H), 5.28 (ddd, J = 1.2, 1.2, 9.6 Hz, 1H), 5.35 (ddd, J = 1.6, 1.6, 16.8 Hz, 1H), 5.78 (ddd, J = 6.8, 10, 4, 17.2 Hz, 1H).
(5) Synthesis of 2 - ((R) -2-methoxymethoxy-3-butenyloxy) ethanol
Lithium aluminum hydride (826 mg) was added to a solution of the compound obtained in Example 8- (4) of preparation (4.77 g) in tetrahydrofuran (100 ml) under a nitrogen atmosphere. The mixture was stirred at the same temperature for one hour. Methanol was added dropwise to the reaction solution, and then water was added dropwise. The insoluble matter in the reaction mixture was filtered off through celite, and washed with ethyl acetate. Saturated aqueous sodium chloride was added to the filtrate, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (2.13 g).
1H-NMR (400 MHz, CDCl3) δ (ppm): 2.38 (t, J = 6.0 Hz, 1H), 3.40 (s, 3H), 3.56-3.67 (m, 4H ), 3.72-3.76 (m, 2H), 4.26 (q, J = 6.0 Hz, 1H), 4.63-4.74 (m, 2H), 5.26-5, 36 (m, 2H), 5.76 (ddd, J = 6.8, 10.4, 15.6 Hz, 1H).
(6) Synthesis of oxime of ((R) -2-methoxymethoxy-3-butenyloxy) acetaldehyde
A solution of dimethylsulfoxide (605 µl) in dichloromethane (1 ml) was added dropwise to a solution of oxalyl chloride (633 µl) in dichloromethane (25 ml) under a nitrogen atmosphere at -78 ° C. The reaction solution was stirred at the same temperature for 10 minutes. A solution of the compound obtained in Example 8- (5) of preparation (1 g) in dichloromethane (4 ml) was added dropwise to the reaction solution at the same temperature. The reaction solution was stirred at the same temperature for 45 minutes. Triethylamine (3.81 ml) was added to the reaction solution, followed by heating to room temperature. The reaction solution was stirred at room temperature for one hour. Saturated aqueous ammonium chloride and ethyl acetate were added to the reaction solution, and the organic layer was separated. The organic layer was washed with
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saturated aqueous sodium and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and ethanol (20 ml) and water (5 ml) were added to the residue. Sodium acetate (1.12 g) and hydroxylamine sulfate (1.12 g) were added to the reaction solution, and the mixture was stirred at room temperature for 13 hours. Ethyl acetate and saturated aqueous sodium chloride were added to the reaction solution, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (900 mg).
1H-NMR (400 MHz, CDCl3) δ (ppm): 3.39 (s, 1.5H), 3.40 (s, 1.5H), 3.54-3.58 (m, 2H), 4 , 14-4.16 (m, 1H), 4.22-4.29 (m, 1H), 4.40-4.41 (m, 1H), 4.62-4.74 (m, 2H) , 5.26-5.37 (m, 2H), 5.71-5.81 (m, 1H), 6.93 (t, J = 4.0 Hz, 0.5H), 7.51 (t , J = 5.6 Hz, 0.5H).
(7) to (9) Synthesis of [(3S, 4R, 5R) -3-amino-3- (2-fluorophenyl) -5-methoxymethoxytetrahydropyran-4-yl] methanol
The title compound (1 g) was obtained from the compound obtained in Preparation Example 8- (6) (900 mg), according to Preparation Example 1.
ESI-MS; m / z 286 [M + + H].
1 H-NMR (400 MHz, CDCl 3) δ (ppm): 2.15-2.19 (m, 1H), 3.30-3.42 (m, 6H), 3.75 (dd, J = 3, 2, 12.0 Hz, 1H), 4.13-4.20 (m, 2H), 4.30 (dd, J = 5.6, 10.8 Hz, 1H), 4.69-4.82 (m, 2H), 7.07 (ddd, J = 1.6, 8.4, 12.8 Hz, 1H), 7.20-7.24 (m, 1H), 7.29-7.35 (m, 1H), 7.60-7.65 (m, 1H).
(10) Synthesis of 1-benzoyl-3 - [(3S, 4R, 5R) -3- (2-fluorophenyl) -4-hydroxymethyl-5-methoxymethoxytetrahydropyran-3-yl] thiourea
Benzoyl isocyanate (667 mg) was added to a solution of the compound obtained in Example 8- (9) of preparation (1 g) in dichloromethane (25 ml), and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (1.45 g).
ESI-MS; m / z 471 [M + + Na].
1H-NMR (400 MHz, CDCl3) δ (ppm): 2.30-2.50 (ma, 1H), 3.0-3.2 (ma, 1H), 3.38-3.48 (m, 1H), 3.45 (s, 3H), 3.604.05 (m, 3H), 4.20-4.34 (m, 2H), 4.77 (s, 2H), 7.03-7.09 (m, 1H), 7.15-7.20 (m, 1H), 7.28-7.35 (m, 1H), 7.49-7.54 (m, 3H), 7.60-7 , 65 (m, 1H), 7.86-7.90 (m, 2H), 8.92 (s, 1H), 11.7 (s, 1H).
(11) Synthesis of N - [(4aS, 5R, 8aR) -8a- (2-fluorophenyl) -5-hydroxy-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia- 1-azanaphthalen-2il] benzamide
Concentrated hydrochloric acid (2 ml) was added to a solution of the compound obtained in Example 8- (10) of preparation (1.45 g) in methanol (20 ml), and the mixture was heated at reflux for one hour. The reaction solution was returned to room temperature and concentrated under reduced pressure. Ethyl acetate and aqueous sodium bicarbonate were added to the residue, and the organic layer was separated. The organic layer was washed with saturated aqueous sodium chloride and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (895 mg).
ESI-MS; m / z 387 [M + + H].
1H-NMR (400 MHz, CDCl3) δ (ppm): 2.82 (dd, J = 4.0, 12.8 Hz, 1H), 2.97-3.02 (m, 1H), 3.26 -3.34 (m, 2H), 3.72 (d, J = 12.0 Hz, 1H), 3.87 (dd, J = 4.8, 6.8 Hz, 1H), 4.09- 4.16 (m, 2H), 7.08-7.14 (m, 1H), 7.17-7.21 (m, 1H), 7.32-7.39 (m, 2H), 7, 42-7.46 (m, 2H), 7.49-7.54 (m, 1H), 8.15-8.18 (m, 2H).
(12) Synthesis of N - [(4aS, 5S, 8aS) -5-fluoro-8a- (2-fluorophenyl) -4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia- 1-azanaphthalen-2il] benzamide
[Bis (2-Methoxyethyl) amino] sulfur trifluoride (892 µl) was added dropwise to a solution of the compound obtained in Example 8- (11) of preparation (895 mg) in dichloromethane (25 ml) under cooling with ice. The reaction solution was stirred at the same temperature for two hours. Aqueous sodium bicarbonate and chloroform were added to the reaction solution, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (255 mg). The recovered crude material (335 mg) was subjected to the same reaction as described above, to obtain the title compound (120 mg).
ESI-MS; m / z 389 [M + + H].
1H-NMR (400 MHz, CDCl3) δ (ppm): 2.88 (dd, J = 3.2, 13.2 Hz, 1H), 3.12-3.25 (m, 2H), 3.56 -3.62 (m, 1H), 3.74-3.78 (m, 1H), 4.18 (d, J = 12.0 Hz, 1H), 4.32 (dd, J = 5.2 , 10.8 Hz, 1H), 4.96-5.16 (m, 1H), 7.10-7.16 (m, 1H), 7.19-7.23 (m, 1H), 7, 34-7.47 (m, 4H), 7.50-7.55 (m, 1H), 8.14-8.24 (m, 2H).
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(13) Synthesis of (4aS, 5S, 8aS) -5-fluoro-8a- (2-fluorophenyl) -4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen -2-ylamine
1,8-Diazabicyclo [5,4,0] -7-undecene (312 µl) was added to a solution of the compound obtained in Example 8- (12) of preparation (370 mg) in methanol (13 ml), and the mixture was heated at reflux for eight hours. The reaction solution was returned to room temperature and concentrated under reduced pressure. The residue was purified by
5 NH-silica gel column chromatography to obtain the title compound (262 mg).
ESI-MS; m / z 285 [M + + H].
1H-NMR (400 MHz, CDCl3) δ (ppm): 2.81 (dd, J = 3.6, 12.4 Hz, 1H), 2.95-3.02 (m, 1H), 3.11 -3.15 (m, 1H), 3.49-3.56 (m, 1H), 3.69-3.84 (m, 1H), 4.08-4.12 (m, 1H), 4 , 25 (dd, J = 5.6, 10.8 Hz, 1H), 4.50-4.65 (ma, 2H), 4.80-4.98 (m, 1H), 7.05 (ddd , J = 1.2, 8.0, 12.8 Hz, 1H), 7.12-7.17 (m, 1H), 7.27-7.34 (m, 2H).
10 (14) to (15) Synthesis of [(4aS, 5S, 8aS) -8a- (5-amino-2-fluorophenyl) -5-fluoro-4,4a, 5,6,8,8a-hexahydro-7 -oxa-3-tia-1azanaftalen-2-yl] tert-butyl carbamate
The title compound (195 mg) was obtained from the compound obtained in Preparation Example 8- (13) (262 mg) according to Preparation Example 1.
ESI-MS; m / z 400 [M + + H].
1 H NMR (400 MHz, CDCl3) δ (ppm): 1.52 (s, 9H), 2.82-2.87 (m, 1H), 3.02-3.10 (m, 2H), 3.53 (dd, J = 4.0, 10.4 Hz, 1H), 3.64 (sa, 2H), 3.65-3.68 (m, 1H), 4.09 (dd, J = 1.6, 11.6 Hz, 1H), 4.26 (dd, J = 6.0, 10.8 Hz, 1H), 4.86-5.05 (m, 1H), 6.49 (dd , J = 2.4, 6.8 Hz, 1H), 6.56-6.60 (m, 1H), 6.88 (dd, J = 8.4, 12.0 Hz, 1H).
Preparation Example 9
Synthesis of (-) - [(4aR *, 5R *, 8aS *) - 8a- (5-amino-2-fluorophenyl) -5-methylctahydro-7-oxa-3-thia-1-azanaphthalen-2-yl] carbamate
20-tert-butyl and (-) - [(4aR *, 5S *, 8aS *) - 8a- (5-amino-2-fluorophenyl) -5-methyl octahydro-7-oxa-3-thia-1-azanaphthalen- 2il] tert-butyl carbamate
[Formula 34]
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(1) Synthesis of 4- (2,2-dimethoxyethoxy) -3-methyl-1-butene
Sodium hydride (60% by weight, 928 mg) was added to a solution of 2-methyl-3-buten-1-ol (2 g) in DMF (30 ml) under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. Bromoacetaldehyde dimethyl acetal 5 (5.45 ml) was added dropwise to the reaction solution at the same temperature. The reaction solution was stirred for 16 hours with gradual heating to room temperature. Ethyl acetate and aqueous sodium chloride were added to the reaction solution, and the organic layer was separated. The same operation was performed at the same scale. The combined organic layers were washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The organic layer was concentrated under pressure.
10 reduced, and the residue was purified by silica gel column chromatography to obtain the title compound (4.92 g).
1H-NMR (400 MHz, CDCl3) δ (ppm): 1.02 (d, J = 6.8 Hz, 3H), 2.45-2.52 (m, 1H), 3.32 (dd, J = 7.2, 9.2 Hz, 1H), 3,363.40 (m, 2H), 3.40 (s, 6H), 3.49 (d, J = 4.8 Hz, 1H), 4.51 (t, J = 4.8 Hz, 1H), 4.99-5.09 (m, 2H), 5.77 (ddd, J = 17.2, 10.8, 6.4 Hz, 1H).
15 (2) Synthesis of oxime of (2-methyl-3-butenyloxy) acetaldehyde
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A solution of the compound obtained in Example 9- (1) of preparation (4.92 g) in formic acid / water (20 ml / 5 ml) was stirred at room temperature for 16 hours. Ethanol (30 ml), water (10 ml), sodium acetate (4.63 g) and hydroxylamine sulfate (4.63 g) were added to the reaction solution, and the mixture was stirred at room temperature for eight hours. Saturated aqueous sodium chloride and ethyl acetate were added to the reaction solution, and the organic layer was separated. The organic layer was washed again with saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (1.57 g).
1H-NMR (400 MHz, CDCl3) δ (ppm): 1.02 (d, J = 7.2 Hz, 1.5H), 1, 04 (d, J = 6.4 Hz, 1.5H), 2.44-2.51 (m, 1H), 3,283.41 (m, 2H), 4.09 (d, J = 6.4 Hz, 1H), 4.33 (d, J = 3.6 Hz , 1H), 5.01-5.11 (m, 2H), 5.72-5.82 (m, 1H), 6.90 (t, J = 3.6 Hz, 0.5H), 7, 45 (sa, 1H), 7.49 (t, J = 6.4 Hz, 0.5 Hz).
(3) to (7) Synthesis of (±) -N - [(4aR *, 5S *, 8aS *) - 8a- (2-fluorophenyl) -5-methyl-4,4a, 5,6,8,8a -hexahydro-7-oxa-3-thia-1azanaftalen-2-yl] benzamide and (±) -N - [(4aR *, 5R *, 8aS *) - 8a- (2-fluorophenyl) -5-methyl-4 , 4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1azanaftalen-2-yl] benzamide
A mixture of the title compound (2.15 g) was obtained from the compound obtained in Preparation Example 9- (2) (1.57 g), according to Preparation Example 8.
ESI-MS; m / z 385 [M + + H].
(8) to (9) Synthesis of (±) -N - [(4aR *, 5S *, 8aS *) - 8a- (2-fluoro-5-nitrophenyl) -5-methyl-4,4a, 5,6 , 8,8a-hexahydro-7-oxa-3-thia-1azanaftalen-2-yl] benzamide and (±) -N - [(4aR *, 5R *, 8aS *) - 8a- (2-fluoro-5- nitrophenyl) -5-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa3-thia-1-azanaphthalen-2-yl] benzamide
The title compound (±) -N - [(4aR *, 5S *, 8aS *) - 8a- (2-fluoro-5-nitrophenyl) -5-methyl-4,4a, 5,6,8,8a- hexahydro-7-oxa-3-thia-1azanaftalen-2-yl] benzamide (440 mg) and the title compound (±) -N - [(4aR *, 5R *, 8aS *) - 8a- (2-fluoro -5-nitrophenyl) -5methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-2-yl] benzamide (1.37 g) were obtained from compound obtained in Preparation Example 9- (7) (2.15 g), according to Preparation Example 8.
ESI-MS; m / z 426 [M "+ H].
(10) Synthesis of (±) - [(4aR *, 5S *, 8aS *) - 8a- (5-amino-2-fluorophenyl) -5-methyl-4,4a, 5,6,8,8a-hexahydro Tert-butyl-7-oxa-3-thia-1-appleftalen-2-yl] carbamate
The title compound (225 mg) was obtained from (±) -N - [(4aR *, 5S *, 8aS *) - 8a- (2-fluoro-5-nitrophenyl) -5-methyl4,4a, 5 , 6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-2-yl] benzamide obtained in Preparation Example 9- (9) (440 mg), according to Preparation Example 8.
ESI-MS; m / z 396 [M + + H].
(11) Synthesis of (±) - [(4aR *, 5R *, 8aS *) - 8a- (5-amino-2-fluorophenyl) -5-methyl-4,4a, 5,6,8,8a-hexahydro Tert-butyl-7-oxa-3-thia-1-appleftalen-2-yl] carbamate
The title compound (953 mg) was obtained from (±) -N - [(4aR *, 5R *, 8aS *) - 8a- (2-fluoro-5-nitrophenyl) -5-methyl4,4a, 5 , 6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-2-yl] benzamide obtained in Preparation Example 9- (9) (1.37 g), according to Preparation Example 8 .
ESI-MS; m / z 396 [M + + H].
(12) Synthesis of (-) - [(4aR *, 5S *, 8aS *) - 8a- (5-amino-2-fluorophenyl) -5-methyl-4,4a, 5,6,8,8a-hexahydro Tert-butyl-7-oxa-3-thia-1-appleftalen-2-yl] carbamate
The compound obtained in Example 9- (10) of preparation was purified by CHIRALPAK ™ AD-H (mobile phase: ethanol, flow rate: 10 ml / min.), And the fraction was collected with a retention time of 12.5 14.7 minutes to obtain the title compound. The same operation was repeated to obtain the title compound (100 mg;> 99% ee) from the crude material (225 mg).
H-NMR (400 MHz, CDCl3) δ (ppm): 0.92 (d, J = 6.8 Hz, 3H), 1.45 (s, 9H), 2.01-2.07 (m, 1H ), 2.78-2.83 (m, 2H), 3,233.30 (m, 1H), 3.39-3.44 (m, 1H), 3.63-3.71 (m, 2H), 4.12 (d, J = 12.8 Hz, 1H), 6.56-6.60 (m, 1H), 6.86 (dd, J = 8.8, 11.6 Hz, 1H), 7 , 05-7.07 (m, 1 H).
ESI-MS; m / z 396 [M + + H].
(13) Synthesis of (-) - [(4aR *, 5R *, 8aS *) - 8a- (5-amino-2-fluorophenyl) -5-methyl-4,4a, 5,6,8,8a-hexahydro Tert-butyl-7-oxa-3-thia-1-appleftalen-2-yl] carbamate
The compound obtained in Example 9- (11) of preparation was purified by CHIRALCEL ™ OJ-H (mobile phase: hexane: ethanol = 1: 1, flow rate: 10 ml / min.), And the fraction was collected with time Retention from 21.8 to 41.7 minutes
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to get the title compound. The same operation was repeated to obtain the title compound (230 mg;> 99% ee) from the crude material (500 mg).
1 H-NMR (400 MHz, CDCl3) δ (ppm): 0.92 (d, J = 6.4 Hz, 3H), 1.52 (s, 9H), 2.20-2.34 (m, 1H), 2.56-2.60 (m, 1H), 2.75-2.87 (m, 2H), 3.28 (t, J = 11.6 Hz, 1H), 3.65 (sa , 2H), 3.67 (d, J = 12.0 Hz, 1H), 3.96 (dd, J = 4.8, 11.2 Hz, 1H), 5 4.11 (dd, J = 1 , 6, 12.0 Hz, 1H), 6.54-6.60 (m, 2H), 6.82-6.88 (m, 1H).
ESI-MS; m / z 396 [M + + H].
Synthesis of (-) - [(4aS *, 5R *, 8aS *) - 8a- (5-amino-2-fluorophenyl) -5-methoxy-4,4a, 5,6,8,8a-hexahydro-7- tert-butyl oxa-3-thia-1azanaftalen-2-yl] carbamate
10 [Formula 35] image32
(1) Synthesis of 1- [2- (tert-butyldimethylsilyloxy) ethoxy] -3-buten-2-ol
A solution of oxalyl chloride (8.38 ml) in dichloromethane (470 ml) was cooled to -78 ° C under a nitrogen atmosphere. A solution of dimethylsulfoxide (8.01 ml) in dichloromethane (10 ml) was added dropwise to the reaction solution at the same temperature. The reaction solution was stirred at the same temperature for 10 minutes. A solution of 2- [2- (tert-butyldimethylsilyloxy) ethoxy] ethanol (25.9 g) in dichloromethane (20 ml) was added dropwise to the reaction solution at the same temperature. The reaction solution was stirred at the same temperature for 30 minutes. Triethylamine (52.1 ml) was added to the reaction solution at the same temperature. The reaction solution was stirred for one hour while gradually returning to room temperature. Aqueous ammonium chloride was added to the reaction solution, and the organic layer was separated. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The organic layer was filtered through a silica pad, and the filtrate was concentrated. Was added
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tetrahydrofuran (500 ml) to the residue. The reaction solution was cooled to -78 ° C under a nitrogen atmosphere. Vinylmagnesium chloride (148 ml, 1.38 M solution in tetrahydrofuran) was added dropwise to the reaction solution at the same temperature. The reaction solution was heated to room temperature with stirring for six hours. Aqueous ammonium chloride and ethyl acetate were added to the reaction solution, and the organic layer was separated. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (10.03 g).
1H-NMR (400 MHz, CDCl3) δ (ppm): 0.08 (s, 6H), 0.91 (s, 9H), 2.82 (d, J = 3.2 Hz, 1H), 3, 38 (dd, J = 8.0, 10.0 Hz, 1H), 3.57-3.63 (m, 3H), 3.78 (t, J = 5.2 Hz, 2H), 4.29 -4.36 (m, 1H), 5.19 (ddd, J = 1.6, 1.6, 10.8 Hz, 1H), 5.36 (ddd, J = 1.6, 1.6, 15.6 Hz, 1H), 5.83 (ddd, J = 5.2, 10.4, 15.6 Hz, 1H).
(2) Synthesis of tert-butyl- [2- (2-methoxy-3-butenyloxy) ethoxy] dimethylsilane
Sodium hydride (357 mg, 60% by weight) was added to a solution of the compound obtained in Example 10- (1) of preparation (2 g) in DMF (20 ml) under ice cooling, and the mixture was stirred at the same temperature for one hour. Methyl iodide (1.01 ml) was added to the reaction solution at the same temperature. The reaction solution was stirred at the same temperature for one hour. Aqueous ammonium chloride and ethyl acetate were added to the reaction solution, and the organic layer was separated. The organic layer was washed with saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (1.30 g).
1 H-NMR (400 MHz, CDCl 3) δ (ppm): 0.06 (s, 6H), 0.89 (s, 9H), 3.34 (s, 3H), 3.49-3.76 (m , 4H), 3.76-3.81 (m, 3H), 5.25-5.33 (m, 2H), 5.72 (ddd, J = 7.2, 10.4, 15.2 Hz , 1 HOUR).
(3) Synthesis of 2- (2-methoxy-3-butenyloxy) ethanol
Tetrabutylammonium fluoride (7.47 ml, 1 M solution in tetrahydrofuran) was added dropwise to a solution of the compound obtained in Example 10- (2) of preparation (1.3 g) in tetrahydrofuran (25 ml) under cooling with ice. The reaction solution was stirred at the same temperature for 10 minutes. The reaction solution was returned to room temperature and stirred further for five hours. Saturated aqueous sodium chloride and ethyl acetate were added to the reaction solution, and the organic layer was separated. Ethyl acetate was added to the aqueous layer, and the organic layer was separated. The organic layers were combined and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (500 mg).
1H-NMR (400 MHz, CDCl3) δ (ppm): 2.41 (s, 1H), 3.35 (s, 3H), 3.54-3.57 (m, 2H), 3.61-3 , 64 (m, 2H), 3.72-3.75 (m, 2H), 3.79-3.84 (m, 1H), 5.28-5.35 (m, 2H), 5.71 (ddd, J = 7.6, 10.4, 15.6 Hz, 1H).
(4) Synthesis of oxime of (2-methoxy-3-butenyloxy) acetaldehyde
The title compound (280 mg) was obtained from the compound obtained in Preparation Example 10- (3) (500 mg), according to Preparation Example 8.
1H-NMR (400 MHz, CDCl3) δ (ppm): 3.34 (s, 1.5H), 3.35 (s, 1.5H), 3.50-3.54 (m, 2H), 3 , 78-3.84 (m, 1H), 4.10-4.16 (m, 1H), 4.40 (d, J = 4.0 Hz, 1H), 5.28-5.36 (m , 2H), 5.66-5.76 (m, 1H), 6.94 (t, J = 3.2 Hz, 0.5H), 7.51 (t, J = 5.2 Hz, 0, 5H).
(5) to (12) Synthesis of (±) - [(4aS *, 5R *, 8aS *) - 8a- (5-amino-2-fluorophenyl) -5-methoxy-4,4a, 5,6,8 , Tert-butyl 8a-hexahydro-7-oxa-3-thia-1-appleftalen-2-yl] carbamate
The title compound (74 mg) was obtained from the compound obtained in Preparation Example 10- (4) (280 mg), according to Preparation Example 9.
ESI-MS; m / z 412 [M + + H].
(13) Synthesis of (-) - [(4aS *, 5R *, 8aS *) - 8a- (5-amino-2-fluorophenyl) -5-methoxy-4,4a, 5,6,8,8a-hexahydro Tert-butyl-7-oxa-3-thia-1-appleftalen-2-yl] carbamate
The compound obtained in Example 10- (12) of preparation was purified by CHIRALCEL ™ OJ-H (mobile phase: hexane: ethanol = 1: 1, flow rate: 10 ml / min.), And the fraction was collected with time retention time of 18.6 to 22.0 minutes to obtain the title compound. The same operation was repeated to obtain the title compound (25 mg;> 99% ee) from the crude material (70 mg).
1H-NMR (400 MHz, CDCl3) δ (ppm): 1.52 (s, 9H), 2.77 (dd, J = 7.6, 12.8 Hz, 1H), 2.84-2.89 (m, 1H), 3.10 (dd, J = 3.2, 12.8 Hz, 1H), 3.32 (dd, J = 10.4, 10.4 Hz, 1H), 3.48 ( s, 3H), 3.61-3.75 (m, 2H), 4.08 (dd, J = 1.2, 12.0 Hz, 1H), 4.29 (dd, J = 4.8, 10.8 Hz, 1H), 6.53 (dd, J = 3.2, 6.4 Hz, 1H), 6.55-6.59 (m, 1H), 6.86 (dd, J = 8 , 4, 12.0 Hz, 1H).
E09817719
06-18-2015
ESI-MS; m / z 412 [M + + H].
Synthesis of (±) - [(2R *, 4aR, 8aS) -8a- (5-amino-2-fluorophenyl) -4-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa- 3-thia-1-azanaphthalen-2-yl] tert-butyl carbamate image33
(1) to (10) Synthesis of (±) - [(2R *, 4aR, 8aS) -8a- (5-amino-2-fluorophenyl) -4-methyl-4,4a, 5,6,8,8a tert-butylhexahydro-7-oxa-3-thia-1azanaftalen-2-yl] carbamate
The title compound (384 mg) was obtained from trans-3-penten-1-ol (4.71 g), according to Preparation Example 9.
10 1 H-NMR (400 MHz, CDCl3) δ (ppm): 1.18 (d, J = 7.2 Hz, 3H), 1.53 (s, 9H), 1.85-1.96 (m , 1H), 2.80 (ddd, J = 4.0, 4.0, 12.0 Hz, 1H), 3.22 (qd, J = 7.2, 3.2 Hz, 1H), 3, 61-3.70 (m, 3H), 4.05-4.17 (m, 2H), 6.54-6.58 (m, 2H), 6.83-6.88 (m, 1H).
ESI-MS; m / z 396 [M ++ H].
Preparation Example 12
Synthesis of 5-difluoromethyl-pyrazin-2-carboxylic acid [Formula 37] image34
(1) Synthesis of t-butyl 5-methylpyrazin-2-carboxylate
Boron-diethyl ether trifluoride complex (91.7 µl) was added dropwise to a suspension of acid 2
20 methylpyrazin-5-carboxylic acid (1 g) and tert-butyl 2,2,2-trichloroacetimidate (4.75 g) in tetrahydrofuran (20 ml) under ice cooling. The reaction solution was heated to room temperature and stirred for two hours. A saturated solution of sodium chloride and ethyl acetate was added to the reaction solution, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, and the insoluble matter was filtered off. The filtrate was concentrated and purified by silica gel column chromatography.
25 to obtain the title compound (1.4 g).
1H-NMR (CDCl3) δ (ppm): 1.65 (s, 9H), 2.65 (s, 3H), 8.57 (d, J = 1.2 Hz, 1H), 9.10 (d , J = 1.6 Hz, 1H).
(2) Synthesis of t-butyl 5 - ((E) -2-dimethylaminovinyl) pyrazin-2-carboxylate
A mixture of t-butyl 5-methylpyrazin-2-carboxylate (1.35 g), N, N-dimethylformamide (25 ml) and dimethyl acetal of N, N-dimethylsulfonamide (25 ml) was stirred at 130 ° C for five hours. The reaction solution was cooled to room temperature and diluted with ethyl acetate. The mixture was washed with a saturated solution of sodium chloride three times. The organic layer was dried over anhydrous magnesium sulfate, and the insoluble matter was filtered off. The filtrate was concentrated, and the residue was purified by silica gel column chromatography to obtain the title compound (648 mg).
1 H-NMR (CDCl3) δ (ppm): 1.63 (s, 9H), 3.00 (s, 6H), 5.16 (d, J = 12.8 Hz, 1H), 7.72 ( d, J = 12.8 Hz, 1H), 8.16 (d, J = 1.2 Hz, 1H), 8.81 (d, J = 1.6 Hz, 1H).
(3) Synthesis of t-butyl 5-formylpyrazin-2-carboxylate
Sodium periodate (1.67 g) was added to a solution of t-butyl 5 - ((E) -2-dimethylamino-vinyl) pyrazin-2-carboxylate (645 mg) in 50% tetrahydrofuran-water (26 ml), and the mixture was stirred at room temperature for four hours. A solution of sodium bicarbonate and ethyl acetate was added to the reaction solution, and the organic layer was separated. The organic layer was washed with a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The insoluble matter was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to obtain the title compound (249 mg).
1H-NMR (CDCl3) δ (ppm): 1.68 (s, 9H), 9.25 (d, J = 1.2 Hz, 1H), 9.36 (d, J = 1.6 Hz, 1H ), 10.2 (s, 1 H).
(4) Synthesis of t-butyl 5-difluoromethylpyrazin-2-carboxylate
[Bis (2-Methoxyethyl) amino] sulfur trifluoride (662 µl) was added dropwise to a solution of t-butyl 5-formylpyrazine-2-carboxylate (249 mg) in dichloromethane (12 ml) under a nitrogen atmosphere under ice cooling. The reaction solution was stirred for two hours while gradually returning to room temperature. A solution of sodium bicarbonate and ethyl acetate was added to the reaction solution, and the organic layer was separated. The organic layer was washed with a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The insoluble matter was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to obtain the title compound (175 mg).
1H-NMR (CDCl3) δ (ppm): 1.67 (s, 9H), 6.75 (t, J = 54.4 Hz, 1H), 9.02 (d, J = 0.8 Hz, 1H ), 9.25 (d, J = 0.8 Hz, 1H).
(5) Synthesis of 5-difluoromethylpyrazin-2-carboxylic acid
Trifluoroacetic acid (1 ml) was added to a solution of t-butyl 5-difluoromethylpyrazin-2-carboxylate (175 mg) in dichloromethane (1 ml), and the mixture was stirred at room temperature for five hours. Ether and 5 N sodium hydroxide were added to the reaction solution. The aqueous layer was separated and made acidic with 5 N hydrochloric acid. Ethyl acetate was added to the aqueous layer, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, and the insoluble matter was filtered off. The filtrate was concentrated to obtain the title compound (100 mg).
1 H-NMR (CDCl 3) δ (ppm): 6.80 (t, J = 54.4 Hz, 1 H), 9.02 (s, 1 H), 9.47 (s, 1 H).
Preparation Example 13
Synthesis of [(4aR, 6R, 8aS) -8a- (5-amino-2-fluorophenyl) -6-hydroxymethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1azanaftalen -2-yl] tert-butyl carbamate
[Formula 38] (1) Synthesis of (R) -1-benzyloxy-4-penten-2-ol image35
Ether (100 ml) and copper (I) iodide (580 mg) were added to a solution of (R) -benzyl glycidyl ether (10.0 g) in THF (100 ml). The mixture was cooled to -78 ° C, and vinylmagnesium chloride (1.38 M, 53.0 ml) was added dropwise. The mixture was stirred overnight with gradual heating to room temperature. Ice was added to the reaction solution, and a solution of ammonium chloride was subsequently added. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with a solution of ammonium chloride. The insoluble matter was removed by filtration through celite, and the solvent was evaporated under reduced pressure to obtain the title compound (12.5 g).
1H-NMR (400 MHz, CDCl3) δ (ppm): 1.59 (d, J = 2.0 Hz, 1H), 2.25-2.29 (m, 2H), 3.38 (dd, J = 7.2, 9.2 Hz, 1H), 3.52 (dd, J = 3.2, 9.2 Hz, 1H), 3.86-3.91 (m, 1H), 4.56 ( s, 2H), 5.08-5.15 (m, 2H), 5.78-5.88 (m, 1H), 7.28-7.38 (m, 5H).
(2) Synthesis of [(R) -2- (2,2-diethoxyethoxy) -4-pentenyloxymethyl] benzene
(R) -1-Benzyloxy-4-penten-2-ol (3.13 g) was dissolved in DMF (32 ml), and sodium hydride (60%, 0.91 g) was added in an ice bath . After stirring at the same temperature for 30 minutes, bromoacetaldehyde diethyl acetal (3.03 ml) was added. The mixture was heated to room temperature and stirred for two hours, and then heated to 50 ° C and stirred for one hour. After cooling to room temperature, ice was added to the reaction solution. The reaction solution was extracted with ethyl acetate. The organic layer was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound. The mixture containing the recovered raw material was reacted under the same conditions. The title compound was obtained by purification by the same method (total yield: 5.00 g).
1H-NMR (400 MHz, CDCl3) δ (ppm): 1.20 (t, J = 7.2 Hz, 3H), 1.21 (t, J = 7.2 Hz, 3H), 2.31- 2.34 (m, 2H), 3.50 (dd, J = 1.2, 5.2 Hz, 2H), 3.53-3.71 (m, 7H), 4.54 (s, 2H) , 4.60 (t, J = 5.2Hz, 1H), 5.02-5.11 (m, 2H), 5.78-5.88 (m, 1H), 7.257.35 (m, 5H) .
(3) Synthesis of oxime of ((R) -1-benzyloxymethyl-3-butenyloxy) acetaldehyde
[(R) -2- (2,2-Diethoxyethoxy) -4-pentenyloxymethyl] benzene (20.0 g) was dissolved in formic acid (160 ml) and water (40 ml), and the mixture was stirred at room temperature for 30 minutes Then, water (161 ml) and ethanol (400 ml) were added, and then hydroxylamine sulfate (6.38 g) and sodium acetate (8.82 g) were added, followed by stirring at room temperature overnight. . Water was added to the reaction solution, and the insoluble matter was dissolved. Then, the excess ethanol was evaporated under reduced pressure. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (13.7 g).
1 H-NMR (400 MHz, CDCl 3) δ (ppm): 2.30-2.35 (m, 2H), 3.47-3.62 (m, 3H), 4.17-4.27 (m, 1H), 4.46-4.47 (m, 1H), 4.55 (d, J = 4.4 Hz, 2H), 5.04-5.11 (m, 2H), 5.74-5 , 85 (m, 1H), 6.94 (t, J = 3.6 Hz, 0.35H), 7.28-7.37 (m, 5H), 7.50 (t, J = 6.0 Hz, 0.65 Hz).
(4) Synthesis of (3aR, 5R) -5-benzyloxymethyl-3,3a, 4,5-tetrahydro-7H-pyrano [3,4-c] isoxazol
Oxime of ((R) -1-benzyloxymethyl-3-butenyloxy) acetaldehyde (13.7 g) was dissolved in dichloromethane (164 ml). A solution of 5% sodium hypochlorite (164 ml) was added dropwise in an ice bath, and the mixture was stirred at the same temperature for two hours. The reaction solution was diluted with water, and the aqueous layer was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (12.2 g).
1H-NMR (400 MHz, CDCl3) δ (ppm): 1.52-1.61 (m, 1H), 2.19 (ddd, J = 0.8, 6.8, 14.4 Hz, 1H) , 3.43-3.50 (m, 2H), 3.56 (dd, J = 6.4, 10.0 Hz, 1H), 3.69-3.75 (m, 1H), 3.79 (dd, J = 8.0, 12.0 Hz, 1H), 4.21 (dd, J = 1.6 Hz, 13.6 Hz, 1H), 4,544.64 (m, 3H), 4.77 (d, J = 13.2 Hz, 1H), 7.30-7.38 (m, 5H).
(5) Synthesis of (3aR, 5R, 7aS) -5-benzyloxymethyl-7a- (2-fluorophenyl) hexahydropyran [3,4-c] isoxazol
Toluene (100 ml) and THF (10 ml) were added to 2-bromofluorobenzene (3.11 g). The reaction solution was cooled to -78 ° C, and n-butyllithium (2.63 M, 6.15 ml) was added dropwise. After stirring at the same temperature for one hour, a mixed solution of (3aR, 5R) -5-benzyloxymethyl3,3a, 4,5-tetrahydro-7H-pyran [3,4-] was added dropwise at the same time c] isoxazole (2.00 g) in toluene (20 ml) and THF (2 ml) and a complex of diethyl boron ether trifluoride (2.03 ml). After stirring at the same temperature for two hours, a solution of ammonium chloride was added to the reaction solution. The aqueous layer was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (2.29 g).
1H-NMR (400 MHz, CDCl3) δ (ppm): 1.51-1.60 (m, 1H), 1.81-1.88 (m, 1H), 3.10-3.18 (m, 1H), 3.49 (dd, J = 4.0, 10.4 Hz, 1H), 3.54-3.58 (m, 2H), 3.70 (d, J = 7.6 Hz, 1H ), 3.88 (d, J = 12.4 Hz, 2H), 4.19 (dd, J = 2.0, 12.4 Hz, 1H), 4.57 (d, J = 12.0, 1H), 4.63 (d, J = 12.0, 1H), 6.30 (s, 1H), 7.03 (ddd, J = 1.2, 8.0, 12.4 Hz, 1H) , 7.16 (dt, J = 1.2, 8.0 Hz, 1H), 7.23-7.37 (m, 6H), 7.93 (dt, J = 1.6, 8.0 Hz , 1 HOUR).
(6) Synthesis of [(2R, 4R, 5S) -5-amino-2-benzyloxymethyl-5- (2-fluorophenyl) tetrahydropyran-4-yl] methanol
Zinc powder (4.36 g) was added to a solution of (3aR, 5R, 7aS) -5-benzyloxymethyl-7a- (2fluorophenyl) hexahydropyran [3,4-c] isoxazole (2.29 g) in acetic acid (50 ml), and the mixture was stirred at room temperature overnight. The insoluble matter was removed by filtration through celite, and the solvent was evaporated under reduced pressure. Ice was added to the residue, followed by neutralization with a 5 N solution of sodium hydroxide. The aqueous layer was extracted with dichloromethane, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (2.08 g).
1H-NMR (400 MHz, CDCl3) δ (ppm): 1.61-1.67 (m, 1H), 1.98-2.08 (m, 1H), 2.30-2.35 (m, 1H), 3.33 (dd, J = 2.8.11.2 Hz, 1H), 3.44 (d, J = 11.2 Hz, 1H), 3.53-3.57 (m, 2H ), 3.62 (dd, J = 6.8, 10.4 Hz, 1H), 3.86-3.90 (m, 1H), 4.27 (dd, J = 2.4, 11.2 Hz, 1H), 4.59 (d, J = 12.0 Hz, 1H), 4.66 (d, J = 12.0 Hz, 1H), 7.06 (ddd, J = 1.6, 8 , 0 Hz, 13.2 Hz, 1H), 7.20 (dt, J = 1.2, 7.6 Hz, 1H), 7.26-7.39 (m, 6H), 7.63 (dt , J = 1.6, 7.6 Hz, 1H).
(7) Synthesis of (4aR, 6R, 8aS) -6-benzyloxymethyl-8a- (2-fluorophenyl) -4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen -2-amine
Benzoyl isothiocyanate (893 µL) was added dropwise to a solution of [(2R, 4R, 5S) -5-amino-2-benzyloxymethyl-5 (2-fluorophenyl) tetrahydropyran-4-yl] methanol (2, 08 g) in dichloromethane (30 ml). The reaction solution was stirred at room temperature for three hours, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography. Several drops of concentrated hydrochloric acid were added to a solution of the resulting intermediate in methanol (40 ml), and the mixture was heated at reflux for five hours. The reaction solution was returned to room temperature, and then the solvent was evaporated under reduced pressure. The residue was dissolved in methanol (40 ml), and DBU (2 ml) was added, followed by heating under reflux for five hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (1.61 g).
1 H-NMR (400 MHz, CDCl3) δ (ppm): 1.51 (ddd, J = 2.4, 3.6, 13.2 Hz, 1H), 1.74-1.84 (m, 1H ), 2.55-2.60 (m, 1H), 2.92-2.98 (m, 2H), 3.47 (dd, J = 4.4, 9.6 Hz, 1H), 3, 62 (dd, J = 6.4, 10.0 Hz, 1H), 3.83 (d, J = 10.8 Hz, 1H), 3.87-3.93 (m, 1H), 4.17 (dd, J = 2.4, 11.2 Hz, 1H), 4.51 (sa, 2H), 4.56 (d, J = 12.0 Hz, 1H), 4.63 (d, J = 12.0 Hz, 1H), 7.02 (ddd, J = 1.6, 8.0, 12.8 Hz, 1H), 7.12 (dt, J = 1.6, 7.6 Hz, 1H ), 7.22-7.37 (m, 7H).
(8) Synthesis of [(4aR, 6R, 8aS) -2-amino-8a- (2-fluorophenyl) -4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1- azanaftalen-6il] methanol
Concentrated hydrochloric acid (25.2 ml) was added to (4aR, 6R, 8aS) -6-benzyloxymethyl-8a- (2-fluorophenyl) -4.4a, 5,6,8,8ahexahydro-7-oxa-3- thia-1-azanaphthalen-2-ylamine (1.26 g), and the mixture was heated at reflux for two hours. After cooling the reaction solution to room temperature, the reaction mixture was poured on ice. The mixture was neutralized with 5 N sodium hydroxide, and the aqueous layer was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residual solid was washed with a mixed solvent of heptane and ether to obtain the title compound (890 mg).
1H-NMR (400 MHz, CDCl3) δ (ppm): 1.40 (ddd, J = 2.0, 6.0, 12.8 Hz, 1H), 1.81-1.90 (m, 1H) , 2.59 (dd, J = 4.4, 14.0 Hz, 1H), 2.95-2.99 (m, 2H), 3.61-3.69 (m, 2H), 3.69 -3.81 (m, 1H), 3.83 (d, J = 11.2 Hz, 1H), 4.17 (dd, J = 2.0, 13.2 Hz, 1H), 7.03 ( ddd, J = 1.2, 8.4, 13.2 Hz, 1H), 7.13 (dt, J = 1.6, 7.6 Hz, 1H), 7.24-7.29 (m, 1H), 7.35 (dt, J = 1.6, 8.0 Hz, 1H).
(9) Synthesis of [(4aR, 6R, 8aS) -2-amino-8a- (2-fluoro-5-nitrophenyl) -4,4a, 5,6,8,8a-hexahydro-7-oxa-3- thia-1-azanaphthalen-6il] methanol
Concentrated sulfuric acid (2.5 ml) was added dropwise to a solution of [(4aR, 6R, 8aS) -2-amino-8a- (2fluorophenyl) -4.4a, 5,6,8,8a-hexahydro -7-oxa-3-thia-1-azanaphthalen-6-yl] methanol (700 mg) in TFA (5 ml) in an ice bath. Then, smoking nitric acid (specific gravity: 1.52, 103 µl) was added dropwise at the same temperature, followed by stirring for one hour. The reaction mixture was poured on ice and made basic with a 5 N solution of sodium hydroxide, followed by stirring at room temperature for two hours. The aqueous layer was extracted with dichloromethane, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain the title compound (1.0 g).
1H-NMR (400 MHz, CDCl3) δ (ppm): 1.46 (ddd, J = 2.4, 4.0, 13.2 Hz, 1H), 1.84-1.94 (m, 1H) , 2.66 (dd, J = 2.4, 12.4 Hz, 1H), 2.93 (dd, J = 4.4, 12.4 Hz, 1H), 2.96-3.02 (m , 1H), 3.63-3.71 (m, 2H), 3.76-3.82 (m, 1H), 3.86 (d, J = 11.2 Hz, 1H), 4.11 ( dd, J = 2.8, 10.4 Hz, 1H), 7.21 (dd, J = 8.8, 10.8 Hz, 1H), 8.19 (ddd, J = 3.2, 4, 0.8.8 Hz, 1H), 8.30 (dd, J = 3.2, 6.8 Hz, 1H).
(10) Synthesis of [(4aR, 6R, 8aS) -8a- (2-fluoro-5-nitrophenyl) -6-hydroxymethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3- tert-butyl thia-1-apple phthalen-2-yl] carbamate
Triethylamine (1 ml) was added to a solution of [(4aR, 6R, 8aS) -2-amino-8a- (2-fluoro-5-nitrophenyl) -4.4a, 5,6,8,8ahexahydro-7- oxa-3-thia-1-azanaphthalen-6-yl] methanol (1.0 g) in THF (100 ml). Then di-tertbutyl dicarbonate (1.28 g) was added, and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel NH-chromatography to obtain the title compound (1.05 g).
1 H-NMR (400 MHz, CDCl3) δ (ppm): 1.47-1.54 (m, 1H), 1.86-1.97 (m, 1H), 2.59 (dd, J = 2 , 8, 12.8 Hz, 1H), 2.86 (dd, J = 3.6, 12.8 Hz, 1H), 3.04-3.08 (m, 1H), 3.67 (d, J = 6.0 Hz, 2H), 3.76-3.82 (m, 1H), 3.83 (d, J = 11.6 Hz, 1H), 4.09 (dd, J = 2.4 , 11.2 Hz, 1H), 7.22-7.25 (m, 1H), 8.20-8.24 (m, 2H).
(11) Synthesis of [(4aR, 6R, 8aS) -8a- (5-amino-2-fluorophenyl-6-hydroxymethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia -1azanaftalen-2-yl) tert-butyl carbamate
Iron powder (121 mg) and a saturated solution of ammonium chloride (1 ml) were added to a solution of [(4aR, 6R, 8aS) -8a- (2-fluoro-5-nitrophenyl) -6-hydroxymethyl- 4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-2-yl] tert-butyl carbamate (120 mg) in ethanol (20 ml). The reaction solution was heated at reflux for 40 minutes and then cooled to room temperature. The insoluble matter was filtered off through celite, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (67 mg).
1H-NMR (400 MHz, CDCl3) δ (ppm): 1.47-1.54 (m, 1H), 1.53 (s, 9H), 1.86-1.96 (m, 1H), 2 , 53 (dd, 2.8, 12.8 Hz, 1H), 2.99 (dd, J = 4.0, 12.4 Hz, 1H), 3.07-3.11 (m, 1H), 3.65-3.81 (m, 4H), 4.18 (dd, J = 1.2, 12.0 Hz, 1H), 6.56-6.60 (m, 2H), 6.84- 6.89 (m, 1 H).
Preparation Example 14
Synthesis of (+) - [(4aR *, 6R *, 8aS *) - 8a- (5-amino-2-fluorophenyl) -6-trifluoromethyl-4,4a, 5,6,8,8a-hexahydro-7- tert-butyl oxa-3-thia-1azanaftalen-2-yl] carbamate image36
(1) Synthesis of (±) - (3aR *, 5R *) - 5-trifluoromethyl-3,3a, 4,5-tetrahydro-7H-pyrano [3,4-c] isoxazol
The title compound (6.6 g) was obtained from 1,1,1-trifluoro-4-penten-2-ol (10.0 g) according to the method of Preparation Example 6.
5 1 H-NMR (400 MHz, CDCl 3) δ (ppm): 1.80 (dd, J = 11.6, 24.4 Hz, 1H), 2.40 (ddd, J = 2.0, 6.4 , 12.8 Hz, 1H), 3.52 (ddd, J = 6.4, 10.8, 22.0 Hz, 1H), 3.85-3.96 (m, 2H), 4.30 ( dd, J = 1.2, 13.6 Hz, 1H), 4.69 (dd, J = 8.4, 10.4 Hz, 1H), 4.88 (d, J = 13.2 Hz, 1H ).
(2) Synthesis of (±) - [(4aR *, 6R *, 8aS *) - 8a- (5-amino-2-fluorophenyl) -6-trifluoromethyl-4,4a, 5,6,8,8a-hexahydro Tert-butyl-7-oxa-3-thia-1-appleftalen-2-yl] carbamate
10 The title compound (1.54 g) was obtained from (±) - (3aR *, 5R *) - 5-trifluoromethyl-3,3a, 4,5-tetrahydro-7H-pyran [3,4c] Isoxazole (2.00 g) according to the method of Preparation Example 6.
1H-NMR (400 MHz, CDCl3) δ (ppm): 1.53 (s, 9H), 1.74-1.79 (m, 1H), 2.50-2.20 (m, 1H), 2 , 57 (dd, J = 2.8, 12.4 Hz, 1H), 2.99-3.07 (m, 2H), 3.66 (s, 2H), 3.85 (d, J = 11 , 6 Hz, 1H), 4.03-4.06 (m, 1H), 4.17 (d, J = 12.0 Hz, 1H), 6.53-6.60 (m, 2H), 6 , 86 (dd, J = 8.8, 12.0 Hz, 1H).
15 (3) Synthesis of (+) - [(4aR *, 6R *, 8aS *) - 8a- (5-amino-2-fluorophenyl) -6-trifluoromethyl-4,4a, 5,6,8,8a- tert-butyl hexahydro-7-oxa-3-thia-1azanaftalen-2-yl] carbamate
(±) - [(4aR *, 6R *, 8aS *) - 8a- (5-amino-2-fluorophenyl) -6-trifluoromethyl-4,4a, 5,6,8,8a-hexahydro-7- was purified tert-butyl oxa-3-thia-1azanaftalen-2-yl] carbamate (25 mg) by CHIRALPAK ™ AD-H (mobile phase: hexane: ethanol = 81:19, flow rate: 10 ml / min.). The fraction was collected with a retention time of 17.7 to 22.6 minutes to obtain the
20 title compound. The same operation was repeated to obtain the title compound (580 mg;> 99% ee) from the racemate (1.45 g).
1H-NMR (400 MHz, CDCl3) δ (ppm): 1.53 (s, 9H), 1.74-1.79 (m, 1H), 2.50-2.20 (m, 1H), 2 , 57 (dd, J = 2.8, 12.4 Hz, 1H), 2.99-3.07 (m, 2H), 3.66 (s, 2H), 3.85 (d, J = 11 , 6 Hz, 1H), 4.03-4.06 (m, 1H), 4.17 (d, J = 12.0 Hz, 1H), 6.53-6.60 (m, 2H), 6 , 86 (dd, J = 8.8, 12.0 Hz, 1H).
25 Preparation Example 15
Synthesis of [(4aR, 6R, 8aS) -8a- (5-amino-2-fluorophenyl) -6-fluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen2-yl] tert-butyl carbamate
[Formula 40] image37
30 (1) Synthesis of [(4aR, 6R, 8aS) -8a- (5-nitro-2-fluorophenyl) -6-fluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3 -tia-1azanaftalen-2-yl] tert-butyl carbamate
[Bis (2-Methoxyethyl) amino] sulfur trifluoride (285 µl) was added dropwise to a solution of [(4aR, 6R, 8aS) -8a- (5
tert-butyl nitro-2-fluorophenyl) -6-hydroxymethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-2-yl] carbamate
obtained in Preparation Example 13 (575 mg) in dichloromethane (55 ml) at -78 ° C. The mixture was stirred overnight with gradual heating to room temperature. Sodium bicarbonate solution was added
to the reaction solution, and the aqueous layer was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel NH-chromatography to obtain the title compound (240 mg).
ESI-MS m / z 444 [M + + H]
(2) Synthesis of [(4aR, 6R, 8aS) -8a- (5-amino-2-fluorophenyl) -6-fluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3- aunt-1
Tert-butyl azanaftalen-2-yl] carbamate The title compound (26 mg) was obtained from [(4aR, 6R, 8aS) -8a- (5-nitro-2-fluorophenyl) -6-fluoromethyl4, Tert-butyl 4,6,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-2-yl] carbamate (39 mg) according to Preparation Example 13.
ESI-MS m / z 414 [M + + H] 10 Preparation Example 16 Synthesis of (±) -N, N-di (tert-butyloxycarbonyl) - [(4aR *, 6R *, 8aS *) - 8a- (5 -bromo-2-fluorophenyl) -6-trifluoromethyl-4,4a, 5,6,8,8ahexahydro-7-oxa-3-thia-1-azanaphthalen-2-yl] amine [Formula 41] image38
15 (1) Synthesis of (±) - (3aR *, 5R *, 7aS *) - 7a- (5-bromo-2-fluorophenyl) -5-trifluoromethyl-hexahydropyran [3,4-c] isoxazole
The title compound (484 mg) was obtained from (±) - (3aR *, 5R *) - 5-trifluoromethyl-3,3a, 4,5-tetrahydro-7Hprano [3,4-c] isoxazole obtained in Preparation Example 14 (300 mg) and 1,3-dibromo-4-fluorobenzene (855 mg) according to the method of Preparation 1- (3).
1H-NMR (400 MHz, CDCl3) δ (ppm): 1.74-1.83 (m, 1H), 2.04-2.10 (m, 1H), 3.12-3.18 (m, 1H), 3.64 (dd, J = 5.2, 8.0
20 Hz, 1H), 3.79 (d, J = 7.6 Hz, 1H), 3.94-4.05 (m, 2H), 4.15 (dd, J = 2.0, 8.0 Hz, 1H), 6.22 (s, 1H), 6.96 (dd, J = 8.4, 11.6 Hz, 1H), 7.43 (ddd, J = 2.8, 4.4, 8.4 Hz, 1H), 8.09 (dd, J = 2.4, 6.8 Hz, 1H).
(2) Synthesis of (±) - [(2R *, 4R *, 5S *) - 5-amino-5- (5-bromo-2-fluorophenyl) -2-trifluoromethyl-tetrahydropyran-4-yl] methanol
The title compound (390 mg) was obtained from (±) - (3aR *, 5R *, 7aS *) - 7a- (5-bromo-2-fluorophenyl) -5trifluoromethylhexahydropyran [3,4-c] isoxazole ( 484 mg) according to Example 1- (4) of preparation.
1H-NMR (400 MHz, CDCl3) δ (ppm): 1.86-1.92 (m, 1H), 2.19-2.30 (m, 1H), 2.37-2.42 (m , 1H), 3.41 (dd, J = 3.2, 11.6 Hz, 1H), 3.51 (d, J = 12.4 Hz, 1H), 3.43 (dd, J = 3, 2, 12.0 Hz, 1H), 4.00-4.05 (m, 1H), 4.23 (dd, J = 2.0, 11.2 Hz, 1H), 6.97 (dd, J = 8.4, 12.0 Hz, 1H), 7.45 (ddd, J = 2.4, 4.4, 8.8 Hz, 1H), 7.84 (dd, J = 2.4, 6 , 8 Hz, 1H).
(3) Synthesis of (±) -N, N-di (tert-butyloxycarbonyl - [(4aR *, 6R *, 8aS *) - 8a- (5-bromo-2-fluorophenyl) -6-trifluoromethyl4,4a, 5 , 6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-2-yl] amine
30 Benzoyl isothiocyanate (156 µL) was added to a solution of (±) - [(2R *, 4R *, 5S *) - 5-amino-5- (5-bromo-2fluorophenyl) -2-trifluoromethyltetrahydropyran-4 -il] methanol (390 mg) in dichloromethane (10 ml), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography. The resulting intermediate was dissolved in methanol (50 ml). Concentrated hydrochloric acid (1.0 ml) was added, and the mixture was heated at reflux for five hours. When the reaction was over, the
The reaction solution was returned to room temperature, and the solvent was evaporated under reduced pressure. Methanol (50 ml) and DBU (500 µl) were added to the residue, followed by heating under reflux for four hours. When the reaction was terminated, the reaction solution was returned to room temperature, and the solvent was evaporated under reduced pressure. The residue was purified by NH-column chromatography on silica gel. The resulting intermediate was dissolved in THF (10 ml), di-tert-butyl dicarbonate (458 mg) and DMAP (385 were added
40 mg), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (138 mg).
1H-NMR (400 MHz, CDCl3) δ (ppm): 1.55 (s, 18H), 1.71-1.75 (m, 1H), 2.29 (ddd, J = 3.2, 12, 0.24.8 Hz, 1H), 2.73 (dd, J = 2.8, 12.8 Hz, 1H), 3.04-3.13 (m, 2H), 4.00-4.13 (m, 3H), 6.94 (dd, J = 8.8, 12.4 Hz, 1H), 7.41 (ddd, J = 2.4, 4.4,
45 8.8 Hz, 1H), 7.82 (dd, J = 2.8, 7.2 Hz, 1H).
Preparation Example 17
Synthesis of N, N-di (tert-butyloxycarbonyl) - [(4aR, 6R, 8aS) -8a- (5-bromo-2-fluorophenyl) -6-fluoromethyl-4,4a, 5,6,8,8ahexahydro- 7-oxa-3-thia-1-azanaphthalen-2-yl] amine
[Formula 42] image39
5 (1) Synthesis of (3aR, 5R, 7aS) -5-benzyloxymethyl-7a- (5-bromo-2-fluorophenyl) hexahydropyran [3,4-c] isoxazol
THF (10 ml) was added to a solution of 1,3-dibromo-4-fluorobenzene (4.31 g) in toluene (100 ml). The mixture was cooled to -78 ° C, and n-butyllithium (2.63 M, 6.15 ml) was added dropwise. After stirring at the same temperature for one hour, a solution of (3aR, 5R) -5-benzyloxymethyl-3,3a, 4,5-tetrahydro-7H-pyran [3,4-c] was added dropwise at the same time. ] isoxazole obtained in Example 13- (4) of preparation (2.00 g) in toluene-THF (10: 1) (20
10 ml) and a complex of boron trifluoride-diethyl ether (2.03 ml). After stirring at the same temperature for two hours, a saturated solution of ammonium chloride was added to terminate the reaction. The aqueous layer was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (2.74 g).
15 H-NMR (400 MHz, CDCl3) δ (ppm): 1.47-1.57 (m, 1H), 1.85 (ddd, J = 1.6, 6.8, 14.0 Hz, 1H ), 3.07-3.12 (m, 1H), 3,473.59 (m, 3H), 3.72 (d, J = 7.6 Hz, 1H), 3.82-3.88 (m, 2H), 4.11 (dd, J = 2.0, 13.2 Hz, 1H), 4.56 (d, J = 12.0 Hz, 1H), 4.63 (d, J = 12.0 Hz, 1H), 6.26 (s, 1H), 6.92 (dd, J = 8.4, 10.0 Hz, 1H), 7.30-7.41 (m, 6H), 8.09 (dd, J = 2.4, 6.8 Hz, 1H).
(2) Synthesis of [(2R, 4R, 5S) -5-amino-2-benzyloxymethyl-5- (5-bromo-2-fluorophenyl) tetrahydropyran-4-yl] methanol
Zinc powder (4.24 g) was added to a solution of (3aR, 5R, 7aS) -5-benzyloxymethyl-7a- (5-bromo-2fluorophenyl) hexahydropyran [3,4-c] isoxazole (2.74 g) in acetic acid (40 ml). After stirring at room temperature overnight, insoluble matter was removed by filtration through celite. The solvent was evaporated under reduced pressure, and ice was added to the residue, followed by neutralization with a 5 N solution of sodium hydroxide. The aqueous layer was extracted with dichloromethane, and the organic layer was dried over sulfate.
25 anhydrous magnesium The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (2.22 g).
1H-NMR (400 MHz, CDCl3) δ (ppm): 1.63-1.67 (m, 1H), 1.95-2.05 (m, 1H), 2.31-2.34 (m, 1H), 3.35 (dd, J = 3.2, 11.6 Hz, 1H), 3.48 (d, J = 11.2 Hz, 1H), 3.53-3.64 (m, 3H ), 3.83-3.87 (m, 1H), 4.21 (dd, J = 2.0, 11.2 Hz, 1H), 4.57-4.67 (m, 2H), 6, 95 (dd, J = 9.2, 12.0 Hz, 1H), 7.24-7.37 (m, 5H), 7.41 (ddd, J = 2.8, 4.4, 9.2 Hz, 1H), 7.80 (dd, J = 2.4, 6.8
30 Hz, 1H).
(3) Synthesis of (4aR, 6R, 8aS) -6-benzyloxymethyl-8a- (5-bromo-2-fluorophenyl) -4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia -1-azanaphthalen-2-ylamine
[(2R, 4R, 5S) -5-amino-2-benzyloxymethyl-5- (5-bromo-2-fluorophenyl) tetrahydropyran-4-yl] methanol (2.22 g) was dissolved in dichloromethane (30 ml), and benzoyl isothiocyanate (776 µl) was added. The mixture was stirred at room temperature for five hours, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain an intermediate. The resulting intermediate was dissolved in methanol (50 ml), and concentrated hydrochloric acid (2 ml) was added. The mixture was heated at reflux for six hours and then cooled to room temperature. The solvent was evaporated under reduced pressure. Methanol (30 ml) and DBU (2 ml) were added to the residue, followed by heating under reflux for three hours. The dissolution of the
The reaction was cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (2.30 g)
1 H-NMR (400 MHz, CDCl3) δ (ppm): 1.50-1.54 (m, 1H), 1.74-1.77 (m, 1H), 2.58-2.60 (m , 1H), 2.90-2.99 (m, 2H), 3.46 (dd, J = 4.4, 10.0 Hz, 1H), 3.62 (dd, J = 6.4, 10 , 0 Hz, 1H), 3.80 (d, J = 10.8 Hz, 1H), 3.85-3.90 (m, 1H), 4,084.11 (m, 1H), 4.54-4 , 64 (m, 2H), 6.91 (dd, J = 8.4, 12.0 Hz, 1H), 7.27-7.38 (m, 6H), 7.45 (dd, J = 2 , 4, 6.8 Hz, 1H).
(4) Synthesis of [(4aR, 6R, 8aS) -8a- (5-bromo-2-fluorophenyl) -6-hydroxymethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3- tert-butyl thia-1-apple phthalen-2-yl] carbamate
Concentrated hydrochloric acid (20 ml) was added to (4aR, 6R, 8aS) -6-benzyloxymethyl-8a- (5-bromo-2-fluorophenyl) 4,4a, 5,6,8,8a-hexahydro-7-oxa -3-thia-1-azanaphthalen-2-ylamine (2.20 g), and the mixture was heated at reflux for two
5 hours. The reaction solution was returned to room temperature, and ice was added to the reaction mixture. The mixture was neutralized with 5 N sodium hydroxide, and the solid generated was collected by a glass filter. The solid was dried under reduced pressure and then dissolved in THF (138 ml). Triethylamine (5.0 ml) and di-tert-butyl dicarbonate (2.06 g) were added, and the mixture was stirred at room temperature for six hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (1.24 g).
1H-NMR (400 MHz, CDCl3) δ (ppm): 1.53 (s, 9H), 1.56-1.59 (m, 1H), 1.85-1.94 (m, 1H), 2 , 55 (dd, J = 2.8, 12.8 Hz, 1H), 2.93 (dd, J = 4.0, 13.2 Hz, 1H), 3.00-3.10 (m, 1H ), 3.65-3.66 (m, 2H), 3.77-3.80 (m, 2H), 4.09-4.13 (m, 1H), 6.97 (dd, J = 8 , 4, 12.0 Hz, 1H), 7.38-7.45 (m, 2H).
(5) Synthesis of [(4aR, 6R, 8aS) -8a- (5-bromo-2-fluorophenyl) -6-fluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3- tia-115 azanaphthalen-2-yl] tert-butyl carbamate
[Bis (2-Methoxyethyl) amino] sulfur (155 µl) trifluoride was added dropwise to a solution of [(4aR, 6R, 8aS) -8a- (5bromo-2-fluorophenyl) -6-hydroxymethyl-4 , 4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-2-yl] carbamate tert-butyl (200 mg) in dichloromethane (5.0 ml) at -78 ° C. The mixture was stirred overnight with gradual heating to room temperature. A solution of sodium bicarbonate was added to the reaction mixture to terminate the reaction. The aqueous layer was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (145 mg).
1H-NMR (400 MHz, CDCl3) δ (ppm): 1.53 (s, 9H), 1.57-1.60 (m, 1H), 1.87-1.96 (m, 1H), 2 , 56 (dd, J = 3.2, 12.8 Hz, 1H), 2.94 (dd, J = 4.0, 12.8 Hz, 1H), 3.04-3.07 (m, 1H ), 3.79 (d, J = 11.6 Hz, 1H), 3.92-3.97 (m, 1H), 4.10-4.13 (m,
1H), 4.34-4.54 (m, 2H), 6.97 (dd, J = 8.4, 11.6 Hz, 1H), 7.37-7.44 (m, 2H).
(6) Synthesis of N, N-di (tert-butyloxycarbonyl) - [(4aR, 6R, 8aS) -8a- (5-bromo-2-fluorophenyl) -6-fluoromethyl-4,4a, 5,6,8 , 8ahexahydro-7-oxa-3-thia-1-azanaphthalen-2-yl] amine
Di-tert-butyl dicarbonate (185 mg) and DMAP (69.1 mg) were added to a solution of [(4aR, 6R, 8aS) -8a- (5bromo-2-fluorophenyl) -6-fluoromethyl-4, 4th, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-2-yl] tert-butyl carbamate (135 mg) in THF (30 ml). The mixture was stirred at room temperature for two hours, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (121 mg).
1H-NMR (400 MHz, CDCl3) δ (ppm): 1.55-1.56 (m, 19H), 1.95-2.05 (m, 1H), 2.69 (dd, J = 2, 8, 12.8 Hz, 1H), 3.05-3.12 (m, 2H), 3.92-4.00 (m, 1H), 4.01 (d, J = 10.8 Hz, 1H ), 4.09 (dd, J = 2.4, 11.6 Hz, 1H), 4.30-4.58 (m, 2H), 6.93 (dd, J =
35 8.4, 12.0 Hz, 1H), 7.39 (ddd, J = 2.4, 4.4, 8.8 Hz, 1H), 7.80 (dd, J = 2.8, 7 , 6 Hz, 1H).
Preparation Example 18
Synthesis of (±) -N-benzoyl-N- (tert-butyloxycarbonyl) - [(4aR *, 8aS *) - 8a- (5-bromo-2-fluorophenyl) -4,4a, 5,6,8,8a -hexahydro-7oxa-3-thia-1-azanaphthalen-2-yl] amine
[Formula 43] image40
(1) Synthesis of (±) - (3aR *, 7aS *) - 7a- (5-bromo-2-fluorophenyl) -hexahydropyran [3,4-c] isoxazol
1,3-Dibromo-4-fluorobenzene (837 mg) was dissolved in a mixture of toluene-THF (10: 1) (15 ml). The mixture was cooled to -78 ° C, and n-butyllithium (2.64 M, 1.19 ml) was added dropwise. After stirring at the same temperature for one hour, a solution of (±) -3,3a, 4,5-tetrahydro-7H-pyran [3,4] was added dropwise at the same time
C) isoxazole obtained in Example 1- (2) of preparation (200 mg) in toluene-THF (10: 1) (5.0 ml) and a complex of boron trifluoride-diethyl ether (394 µl). After stirring at the same temperature for three hours, the reaction was terminated with a solution of ammonium chloride. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (365 mg).
1 H-NMR (400 MHz, CDCl 3) δ (ppm): 1.76-1.91 (m, 2H), 3.03-3.08 (m, 1H), 3.61-3.77 (m, 4H), 4.00-4.06 (m, 2H), 6.28 (s, 1H), 6.93 (dd, J = 8.8, 11.6 Hz, 1H), 7.37-7 , 41 (m, 1H), 8.09 (dd, J = 2.4, 6.8 Hz, 1H).
(2) Synthesis of (±) -N - [(4aR *, 8aS *) - 8a- (5-bromo-2-fluorophenyl) -4,4a, 5,6,8,8a-hexahydro-7-oxa- 3-thia-1-azanaphthalen-2il] benzamide
5 Zinc powder (759 mg) was added to a solution of (±) - (3aR *, 7aS *) - 7a- (5-bromo-2-fluorophenyl) hexahydropyran [3,4c] isoxazole (350 mg) in acid acetic (6.73 ml). After stirring at room temperature overnight, insoluble matter was removed by filtration through celite. The solvent was evaporated under reduced pressure, and the resulting residue was neutralized with 5 N sodium hydroxide in an ice bath. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with brine. The organic layer was dried over anhydrous magnesium sulfate, and the
The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain an intermediate (300 mg). Benzoyl isothiocyanate (133 µl) was added to a solution of the resulting intermediate in dichloromethane (10 ml), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure. Methanol (10 ml) and concentrated hydrochloric acid (several drops) were added to the resulting residue, and the mixture was heated at reflux for two hours. The reaction solution was returned to the
15 room temperature, and the solvent was evaporated under reduced pressure. The resulting residue was neutralized with a solution of sodium bicarbonate, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel NH-chromatography to obtain the title compound (211 mg).
ESI-MS m / z 449 [M + + H]
20 (3) Synthesis of (±) -N-benzoyl-N- (tert-butyloxycarbonyl) - [(4aR *, 8aS *) - 8a- (5-bromo-2-fluorophenyl) -4,4a, 5,6 , 8,8ahexahydro-7-oxa-3-thia-1-azanaphthalen-2-yl] amine
DMAP (86.1 mg) and di-tert-butyl dicarbonate (123 mg) were added to a solution of (±) -N - [(4aR *, 8aS *) - 8a- (5bromo-2-fluorophenyl) - 4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-2-yl] benzamide (211 mg) in THF (10 ml). The mixture was stirred at room temperature overnight, and then the solvent was evaporated under reduced pressure. He
The residue was purified by silica gel column chromatography to obtain the title compound (229 mg).
1H-NMR (400 MHz, CDCl3) δ (ppm): 1.34 (s, 9H), 1.37-1.49 (m, 1H), 2.18-2.27 (m, 1H), 2 , 70 (dd, J = 2.8, 12.8 Hz, 1H), 2.93-2.98 (m, 1H), 3.08 (dd, J = 3.6, 12.8 Hz, 1H ), 3.62-3.67 (m, 1H), 3.66 (d, J = 10.8 Hz, 1H), 4.06-4.08 (m, 2H), 6.94 (dd, J = 8.4, 12.0 Hz, 1H), 7.38-7.47 (m, 3H), 7.52-7.56 (m, 1H), 7.75-7.78 (m, 2H), 7.93 (dd, J = 2.4, 6.8
30 Hz, 1H).
Synthesis of (±) -N, N-di (tert-butyloxycarbonyl) - [(4aR *, 8aS *) - 8a- (4-aminothiophene-2-yl) -4,4a, 5,6,8,8a- hexahydro-7-oxa-3-thia1-azanaphthalen-2-yl] amine image41
35 (1) Synthesis of (±) - (3aR *, 7aS *) - 7a- (4-bromothiophene-2-yl) -hexahydropyran [3,4-c] isoxazole
N-Butyllithium (2.63 M, 2.99 ml) was added dropwise to a solution of 2,4-dibromothiophene (2.00 g) in toluene-THF
(10: 1) (22 ml) at -78 ° C. After stirring at the same temperature for one hour, a solution of (±) -3,3a, 4,5-tetrahydro-7H-pyran [3,4-c] isoxazole obtained in Example 1- (2) of preparation (500 mg) in toluene-THF (10: 1) (10 ml) and a complex of boron trifluoride-diethyl ether (990 µl). After stirring at the same temperature for two hours, a solution of ammonium chloride was added to terminate the reaction. The aqueous layer was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (700 mg).
1 H-NMR (400 MHz, CDCl 3) δ (ppm): 1.74-1.92 (m, 2H), 2.82-2.87 (m, 1H), 3.58-4.03 (m, 6H), 6.96 (d, J = 1.6H, 1H), 7.16 (d, J = 1.6 Hz, 1H).
(2) Synthesis of (±) - (4aR *, 8aS *) - 8a- (4-bromothiophene-2-yl) -4,4a, 5,6,8,8a-hexahydro-7-oxa-3-aunt -1-azanaphthalen-2-ylamine
Zinc powder (1.58 g) was added to a solution of (±) - (3aR *, 7aS *) - 7a- (4-bromothiophene-2-yl) hexahydropyran [3,4c] isoxazole (700 mg) in acetic acid (20 ml). After stirring at room temperature overnight, insoluble matter was removed by filtration through celite. The solvent was evaporated under reduced pressure, and the residue was neutralized with ice and 5 N sodium hydroxide. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography. The resulting intermediate was dissolved in dichloromethane (20 ml), and benzoyl isothiocyanate (324 µl) was added. The mixture was stirred at room temperature overnight, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography. The resulting intermediate was dissolved in methanol (20 ml), and concentrated hydrochloric acid (several drops) was added. The mixture was heated at reflux for six hours and then cooled to room temperature. The solvent was evaporated under reduced pressure. The residue was dissolved in methanol (20 ml), and DBU (1.00 ml) was added, followed by heating under reflux for eight hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel NH-chromatography to obtain the title compound (770 mg).
1H-NMR (400 MHz, CDCl3) δ (ppm): 1.45-1.48 (m, 1H), 2.14 (ddd, J = 4.8, 12.4, 26.0 Hz, 1H) , 2.24-2.30 (m, 1H), 2.62 (dd, J = 3.2, 12.4 Hz, 1H), 3.26 (dd, J = 3.6, 12.4 Hz , 1H), 3.54 (d, J = 11.6 Hz, 1H), 3.57-3.64 (m, 1H), 3.91 (d, J = 11.2 Hz, 1H), 4 , 08-4.12 (m, 1H), 6. 76 (d, J = 1.2 Hz, 1H), 7.12 (d, J = 1.2 Hz, 1H).
(3) Synthesis of (±) -N, N-di (tert-butyloxycarbonyl) - [(4aR *, 8aS *) - 8a- (4-bromothiophene-2-yl) -4,4a, 5,6,8 , 8a-hexahydro-7-oxa-3thia-1-azanaphthalen-2-yl] amine
DMAP (847 mg) and di-tert-butyl dicarbonate (1.51 g) were added to a solution of (±) - (4aR *, 8aS *) - 8a- (4-bromothiophene-2-yl) -4.4a , 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-2-ylamine (770 mg) in THF (10 ml). The mixture was stirred at room temperature for three hours, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (1.07 g).
1H-NMR (400 MHz, CDCl3) δ (ppm): 1.50-1.51 (m, 1H), 1.53 (s, 18H), 2.24 (ddd, J = 4.4, 12, 4, 25.2 Hz, 1H), 2,332.38 (m, 1H), 2.68 (dd, J = 3.2, 12.8 Hz, 1H), 3.33 (dd, J = 3.6 , 13.2 Hz, 1H), 3.56-3.63 (m, 2H), 4.04 (dd, J = 4.4, 11.6 Hz, 1H), 4.11 (d, J = 11.6Hz, 1H), 6.54 (d, J = 1.6 Hz, 1H), 7.16 (d, J = 1.6 Hz, 1H).
(4) Synthesis of (±) -N, N-di (tert-butyloxycarbonyl) - [(4aR *, 8aR *) - 8a- [4- (4,4,5,5-tetramethyl- [1,3, 2] dioxaborolan-2-yl) -thiophene-2-yl] -4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-2-yl] amine
Bis (pinacolato) diboro (2.15 g), potassium acetate (663 mg) and a 1,1'bis (diphenylphosphino) ferrocenopaladium-dichloromethane (138 mg) complex were added to a solution of (±) -N, N-di (tert-butyloxycarbonyl) [(4aR *, 8aS *) - 8a- (4-bromothiophene-2-yl) -4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia -1-azanaftalen-2-yl] amine (900 mg) in DMF (46.9 ml). After replacing with nitrogen, the mixture was stirred at 80 ° C for six hours. The reaction solution was returned to room temperature and diluted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (790 mg).
ESI-MS m / z 581 [M + + H]
(5) Synthesis of (±) -N, N-di (tert-butyloxycarbonyl) - [(4aR *, 8aR *) - 8a- (4-azidothiophene-2-yl) -4,4a, 5,6,8 , 8a-hexahydro-7-oxa-3thia-1-azanaphthalen-2-yl] amine
Sodium azide (177 mg) and copper (II) acetate (99.2 mg) were added to a solution of (±) -N, N-di (tert-butoxycarbonyl) - [(4aR *, 8aR *) - 8a- [ 4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -thiophene-2-yl] -4,4a, 5,6,8,8a-hexahydro-7oxa- 3-thia-1-azanaphthalen-2-yl] amine (790 mg) in methanol (88 ml). The mixture was stirred at room temperature overnight, and then the excess methanol was evaporated under reduced pressure. A solution of ammonium chloride was added to the residue, and the aqueous layer was with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (503 mg).
ESI-MS m / z 518 [M + + H]
(6) Synthesis of (±) -N, N-di (tert-butyloxycarbonyl) - [(4aR *, 8aS *) - 8a- (4-aminothiophene-2-yl) -4,4a, 5,6,8 , 8a-hexahydro-7-oxa-3thia-1-azanaphthalen-2-yl] amine
Zinc powder (133 mg) and ammonium formate (320 mg) were added to a solution of (±) -N, N-di (tert)
5-butyloxycarbonyl) - [(4aR *, 8aR *) - 8a- (4-azidothiophene-2-yl) -4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen -2-yl] amine (503 mg) in methanol (76.2 ml). The mixture was stirred at room temperature overnight, and then the solvent was evaporated under reduced pressure at room temperature or lower. Water was added to the residue, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the
10 title compound (325 mg).
ESI-MS m / z 518 [M + + Na]
(7) Synthesis of (+) - N, N-di (tert-butyloxycarbonyl) - [(4aR *, 8aS *) - 8a- (4-aminothiophene-2-yl) -4,4a, 5,6,8 , 8a-hexahydro-7-oxa-3thia-1-azanaphthalen-2-yl] amine
(±) -N, N-di (tert-butyloxycarbonyl) - [(4aR *, 8aS *) - 8a- (4-aminothiophene-2-yl) -4.4a, 5,6,8,8a- hexahydro-7-oxa-3-aunt
15 1-azanaphthalen-2-yl] amine (32.5 mg) by CHIRALCEL ™ OJ-H (mobile phase: hexane: ethanol = 8: 2, flow rate: 10 ml / min.), And the fraction was collected with a retention time of 14.9 to 23.5 minutes, to obtain the title compound. The same operation was repeated to obtain the title compound (112 mg) from the crude material (325 mg).
1H-NMR (400 MHz, CDCl3) δ (ppm): 1.46-1.48 (m, 1H), 1.53 (s, 18H), 2.16-2.33 (m, 2H), 2 , 64 (dd, J = 2.8, 12.8 Hz,
20 1H), 3.39 (dd, J = 3.6, 12.8 Hz, 1H), 3.55-3.62 (m, 1H), 3.65 (d, J = 11.2 Hz, 1H), 4.03 (dd, J = 4.8, 11.6 Hz, 1H), 4.13 (d, J = 2.8 Hz, 1H), 6.07 (d, J = 2.0 Hz, 1H), 6.67 (d, J = 2.0 Hz, 1H).
Preparation Example 20
Synthesis of N, N-di- (tert-butyloxycarbonyl) - [(4aR, 6R, 8aS) -8a- (5-bromo-2-fluorophenyl) -6-benzyloxymethyl-4,4a, 5,6,8,8ahexahydro -7-oxa-3-thia-1-azanaphthalen-2-yl] amine
25 [Formula 45] image42
Di-tert-butyl dicarbonate (113 mg) and DMAP (63.0 mg) were added to a solution of (4aR, 6R, 8aS) -6-benzyloxymethyl-8a- (5-bromo-2-fluorophenyl) -4,4a , 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-2-ylamine obtained by the method of Example 17- (3) of preparation (80.0 mg) in THF (5, 0 ml) The mixture was stirred at temperature.
30 overnight, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (95.0 mg).
1H-NMR (400 MHz, CDCl3) δ (ppm): 1.54-1.56 (m, 19H), 1.88-1.98 (m, 1H), 2.65-2.67 (m, 1H), 2.99-3.10 (m, 2H), 3.44 (dd, J = 4.4, 9.6 Hz, 1H), 3.62 (dd, J = 10.0, 16, 8 Hz, 1H), 3.85-3.90 (m, 1H), 3.99-4.10 (m, 2H), 4.52-4.64 (m, 2H), 6.92 (dd , J = 8.4, 12.0 Hz, 1H), 7.28-7.39 (m, 6H), 7.79 (dd, J = 2.4, 7.2 Hz, 1H).
35 Preparation Example 21
Synthesis of (±) - [(4aR *, 8aS *) - 8a- (6-amino-2,2-difluorobenzo [1,3] dioxol-4-yl) -4,4a, 5,6,8,8a tert-butylhexahydro-7-oxa-3-thia-1azanaftalen-2-yl] carbamate
[Formula 46] image43
40 (1) Synthesis of (±) - (3aR *, 7aS *) - 7a- (2,2-difluorobenzo [1,3] dioxol-4-yl) hexahydropyran [3,4-c] isoxazole
THF (2.0 ml) was added to a solution of 4-bromo-2,2-difluoro-1,3-benzodioxol (1.96 g) in toluene (20 ml). The mixture was cooled to -78 ° C, and a solution of (±) -3,3a, 4,5-tetrahydro7H-pyran [3,4-c] isoxazole obtained in the Example was added dropwise 1- (2) preparation (500 mg) in toluene-THF (10: 1) (10 ml) and a complex of boron trifluoride-diethyl ether (990 µl). After stirring at the same temperature for two hours, a solution of ammonium chloride was added to terminate the reaction. The aqueous layer was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (873 mg).
1 H-NMR (400 MHz, CDCl 3) δ (ppm): 1.75-1.92 (m, 2H), 3.04-3.09 (m, 1H), 3.63-3.85 (m, 4H), 3.99 (d, J = 12.8 Hz, 1H), 4.03-4.06 (m, 1H), 6.30 (s, 1H), 7.01 (dd, J = 1 , 2, 8.4 Hz, 1H), 7.10 (t, J = 8.4 Hz, 1H), 7.60 (dd, J = 1.2, 8.0 Hz, 1H)
(2) Synthesis of (±) - [(3S *, 4R *) - 3-amino-3- (2,2-difluoro-benzo [1,3] dioxol-4-yl) -tetrahydropyran-4-yl] methanol
Zinc powder (2.01 g) was added to a solution of (±) - (3aR *, 7aS *) - 7a- (2,2-difluoro-benzo [1,3] dioxol-4-yl) hexahydropyran [ 3,4-c] isoxazole (875 mg) in acetic acid (30 ml), and the mixture was stirred at room temperature overnight. The insoluble matter was removed by filtration through celite, and the solvent was evaporated under reduced pressure. Ice was added to the residue, followed by neutralization with a 5 N solution of sodium hydroxide. The aqueous layer was extracted with dichloromethane, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (661 mg).
1H-NMR (400 MHz, CDCl3) δ (ppm): 1.62-1.66 (m, 1H), 2.14-2.20 (m, 1H), 2.22-2.31 (m, 1H), 3.38 (dd, J = 2.4, 11.2 Hz, 2H), 3.56-3.68 (m, 2H), 4.04 (d, J = 11.6 Hz, 1H ), 4.17 (dd, J = 4.4, 11.2 Hz, 1H), 7.05 (dd, J = 1.2, 8.0, 1H), 7.14 (t, J = 8 , 0 Hz, 1H), 7.32 (dd, J = 1.2, 8.0 Hz, 1H).
(3) Synthesis of (±) - (4aR *, 8aS *) - 8a- (2,2-difluorobenzo [1,3] dioxol-4-yl) -4,4a, 5,6,8,8a-hexahydro -7-oxa-3-tia-1azanaftalen-2-ylamine
Benzoyl isothiocyanate (372 µl) was added to a solution of (±) - [(3S *, 4R *) - 3-amino-3- (2,2-difluorobenzo [1,3] dioxol-4-yl) tetrahydropyran- 4-yl] methanol (661 mg) in dichloromethane (9.53 ml). The mixture was stirred at room temperature for three hours, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography. The resulting intermediate was dissolved in methanol (20 ml). Concentrated hydrochloric acid (five drops) was added, and the mixture was heated at reflux for five hours. The reaction solution was cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was dissolved in methanol (20 ml) and DBU (700 µl) was added, followed by heating under reflux for five hours. The reaction solution was cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel to obtain the title compound (3 50 mg).
1H-NMR (400 MHz, CDCl3) δ (ppm): 1.43-1.48 (m, 1H), 2.08-2.19 (m, 1H), 2.64 (dd, J = 2, 8, 12.4 Hz, 1H), 2.74-2.80 (m, 1H), 2.98 (dd, J = 4.4, 12.4 Hz, 1H), 3.69 (ddd, J = 2.4, 11.6, 12.8 Hz, 1H), 3.79 (d, 11.2 Hz, 1H), 3.93 (d, J = 10.8 Hz, 1H), 4.10 (dd, J = 5.2, 11.2 Hz, 1H) 6.99 (dd, J = 2.0, 7.2 Hz, 1H), 7.03-7.09 (m, 2H).
(4) Synthesis of (±) - [(4aR *, 8aS *) - 8a- (2,2-difluoro-6-nitrobenzo [1,3] dioxol-4-yl) -4,4a, 5,6, 8,8a-hexahydro-7-oxa-3-thia-1-apple phthalen-2-yl] tert-butyl carbamate
Smoking nitric acid (7.60 µL) was added to a solution of (±) - (4aR *, 8aS *) - 8a- (2,2-difluorobenzo [1,3] dioxol-4-yl) 4,4a , 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-2-ylamine (50.0 mg) in TFA (1.0 ml) in an ice bath. Then, concentrated sulfuric acid (0.5 ml) was added dropwise. After stirring at the same temperature for one hour, the reaction mixture was poured on ice to terminate the reaction. The mixture was neutralized with 5 N hydroxide. The aqueous layer was extracted with dichloromethane, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain an intermediate. The resulting intermediate was dissolved in THF (10 ml). Di-tert-butyl dicarbonate (66.8 mg) and triethylamine (64.5 µl) were added, and the mixture was stirred at room temperature for one hour. Subsequently, di-tert-butyl dicarbonate (130 mg) and triethylamine (1.00 ml) were added, and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (62.0 mg).
1H-NMR (400 MHz, CDCl3) δ (ppm): 1.51 (s, 9H), 1.55-1.59 (m, 1H), 2.15-2.25 (m, 1H), 2 , 63-2.66 (m, 1H), 2.87-2.89 (m, 2H), 3.65-3.71 (m, 1H), 3.76-3.84 (m, 2H) , 4.10-4.15 (m, 1H), 7.93 (d, J = 2.0 Hz, 1H), 8.05 (d, J = 2.0 Hz, 1H).
ESI-MS m / z 496 [M + + Na]
(5) Synthesis of (±) - [(4aR *, 8aS *) - 8a- (6-amino-2,2-difluorobenzo [1,3] dioxol-4-yl) -4,4a, 5,6, 8,8a-hexahydro-7-oxa-3-thia-1-apple phthalen-2-yl] tert-butyl carbamate
Iron powder (7.09 mg) and a saturated solution of ammonium chloride (1.0 ml) were added to a solution of (±) - [(4aR *, 8aS *) - 8a- (2,2-difluoro -6-nitrobenzo [1,3] dioxol-4-yl) -4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-2-yl] tert-butyl carbamate ( 60.0 mg) in ethanol (20 ml), and the mixture was heated at reflux for 30 minutes. The reaction solution was returned to room temperature, and insoluble matter was removed by filtration.
5 through celite. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (50.0 mg).
ESI-MS m / z 444 [M + + H]
Preparation Example 22
Synthesis of 5- (2-methoxyethoxy) pyrazin-2-carboxylic acid
10 [Formula 47] image44
(1) Synthesis of 2-methoxyethyl 5- (2-methoxyethoxy) -pyrazin-2-carboxylate
60% sodium hydride (27.8 mg) was added to a solution of 2-methoxyethanol (50.2 µl) in DMF (1 ml) under ice cooling, followed by stirring for 10 minutes. A solution of 5-chloropyrazine-2 was added
Methyl carboxylate (100 mg) in DMF (1 ml) to the reaction solution at the same temperature, followed by stirring for one hour and 50 minutes. Acetic acid (50.0 µl) and water were added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (19.7 mg).
1H-NMR (400 MHz, CDCl3) δ (ppm): 3.24 (s, 3H), 3.45 (s, 3H), 3.73-3.81 (m, 4H), 4.53-4 , 61 (m, 4H), 8.34-8.38 (m, 20 1H), 8.86-8.90 (m, 1H).
(2) Synthesis of 5- (2-methoxyethoxy) pyrazine-2-carboxylic acid
Potassium trimethylsilanolate (14.8 mg) was added to a solution of the compound obtained in the previous step (19.7 mg) in tetrahydrofuran (1 ml), and the mixture was stirred at room temperature for one hour. The reaction solution was concentrated under reduced pressure. Water and ethyl acetate were added to the residue, and the aqueous layer was
25 separated. 5M hydrochloric acid was added to the aqueous layer, followed by extraction with chloroform. The organic layer was concentrated under reduced pressure to obtain the title compound (13.2 mg).
1H-NMR (400 MHz, CDCl3) δ (ppm): 3.45 (s, 3H), 3.77-3.82 (m, 2H), 4.60-4.64 (m, 2H), 8 , 24 (d, J = 1.4 Hz, 1H), 8.96 (d, J = 1.4 Hz, 1H).
Example 1
Synthesis of N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-8a-yl ) -4-fluorophenyl] -5cianopyridin-2-carboxamide image45
Oxalyl chloride (140 µl) was added to a suspension of 5-cyanopyridin-2-carboxylic acid (50 mg) in dichloromethane (2 ml) under ice cooling. Tetrahydrofuran (4 ml) was added subsequently at the same temperature, and the solid dissolved completely. After confirming that foaming was completed, the solvent was evaporated under reduced pressure. Tetrahydrofuran (5 ml) was added to the residue to obtain an acid chloride solution. The acid chloride solution prepared above (788 µl) was added to a solution of (-) - [(4aR *, 8aS *) - 8a- (5-amino-2-fluorophenyl) -4,4a, 5, 6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-2-yl] tert-butyl carbamate (14.5 mg) in tetrahydrofuran (5 ml) under ice cooling. After adding pyridine (500 µl) to it
temperature, the mixture was heated to room temperature and stirred for two hours. After finishing the reaction, a solution of sodium bicarbonate was added to the reaction solution. The aqueous layer was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain an amide compound. The resulting amide compound was dissolved in dichloromethane
5 (4 ml), and trifluoroacetic acid (1 ml) was added. The mixture was stirred at room temperature for three hours, and then ice was added. The aqueous layer was neutralized with a solution of sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (8.0 mg).
10 1H-NMR (400 MHz, CDCl3) δ (ppm): 1.45 (ddd, J = 2.0, 4.0, 13.6 Hz, 1H), 2.14 (m, 1H), 2, 65 (dd, J = 2.8, 12.4 Hz, 1H), 2.94 (ddd, J = 4.0, 7.2, 11.6 Hz, 1H), 3.02 (dd, J = 4.0, 12.0 Hz, 1H), 3.69 (m, 1H), 3.77 (d, J = 10.8 Hz, 1H), 4.06 (dd, J = 2.0, 10 , 8 Hz, 1H), 4.10 (m, 1H), 7.09 (dd, J = 8.8, 11.6 Hz, 1H), 7.39 (dd, J = 2.8, 6, 8 Hz, 1H), 8.01 (ddd, J = 2.8, 4.4, 9.2 Hz, 1H), 8.20 (dd, J = 1.6, 8.0 Hz, 1H), 8.42 (dd, J = 0.8, 8.0 Hz, 1H), 8.89 (dd, J = 0.8, 2.0 Hz, 1H), 9.82 (s, 1H).
15 Example 2
Synthesis of N- [3 - ((8S *, 8aR *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-8a-yl) -4-fluorophenyl] -5fluoromethoxypyrazin-2-carboxamide
[Formula 49] image46
The compound obtained in Preparation Example 2 (19.0 mg), N, N-diisopropylethylamine (41.1 µL) and PyBOP (102 mg) were added to a solution of the compound obtained in Preparation Example 1 ( 30.0 mg) in dichloromethane (857 µl). The reaction solution was stirred at room temperature for 16 hours and 30 minutes. Then, the reaction mixture was purified by silica gel column chromatography to obtain an amide compound. The resulting amide compound was dissolved in dichloromethane (643 µl), and acid was added
25 trifluoroacetic (214 μl). The reaction solution was allowed to stand at room temperature for one hour, and then the solvent was evaporated under reduced pressure. A solution of sodium bicarbonate was added to the residue, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (15.4 mg).
1H-NMR (400 MHz, CDCl3) δ (ppm): 1.41-1.48 (m, 1H), 2.08-2.20 (m, 1H), 2.64 (dd, J = 12, 2, 3.5 Hz, 1H), 2.89-2.98
30 (m, 1H), 3.02 (dd, J = 12.2, 5.0 Hz, 1H), 3.64-3.74 (m, 1H), 3.74-3.80 (m, 1H), 4.03-4.13 (m, 2H), 6.08-6.10 (m, 1H), 6.21-6.23 (m, 1H), 7.08 (dd, J = 12.0, 8.8 Hz, 1H), 7.33 (dd, J = 6.8, 2.8 Hz, 1H), 7.99-8.04 (m, 1H), 8.29 (d , J = 1.2 Hz, 1H), 9.08 (d, J = 1.2 Hz, 1H), 9.47 (sa, 1H).
Example 3
Synthesis of N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-8a-yl) -4-fluorophenyl] -535 difluoromethoxypyrazin-2-carboxamide image47
The title compound (14.0 mg) was obtained from the compound obtained in Preparation Example 1 (18.0 mg) and 5-difluoromethoxypyrazin-2-carboxylic acid (24.9 mg) according to the method of Example 2 .
1H-NMR (400 MHz, CDCl3)) δ (ppm): 1.46-1.49 (m, 1H), 2.08-2.16 (m, 2H), 2.65-2.68 (m , 1H), 2.98-3.04 (m, 2H), 3.66-3.72 (m, 1H), 3.81-3.84 (m, 1H), 4.04-4.07 (m, 1H), 7.06-7.12 (m, 1H), 7.36-7.39 (m, 1H), 7.51 (t, J = 71.6 Hz, 1H), 8, 02-8.04 (m, 1H), 8.34 (s, 1H), 9.06 (s, 1H), 9.50 (s, 1H)
Examples 4 to 5
The compounds of Examples 4 to 5 below were synthesized according to Example 2 using the compound of Preparation 5- (9) and the corresponding carboxylic acids, as shown in the following Table 1.
[Table 1]

Example 4

Chemical structure Compound name: N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8ahexahydro-7-oxa-3-thia-1-azanaphthalen-8a- il) -4-trifluoromethoxyphenyl] -5cianopyridin-2-carboxamide

ESI-MS m / z 478 [M ++ H]

Example 5

Chemical structure Compound name: N- [3 - ((8S *, 8aS *) - 2-amino-4,4a, 5,6,8,8ahexahydro-7-oxa-3-thia-1-azanaphthalen-8a- il) -4-trifluoromethoxyphenyl] -5chloropyridin-2-carboxamide

ESI-MS m / z 487 [M ++ H]

Examples 6 to 10
The compounds of Examples 6 to 10 below were synthesized according to Example 2 using the compound of Preparation Example 6- (12) and the corresponding carboxylic acids, as shown in the following Table 2.
[Table 2]

Example 6

Chemical structure Compound name: N- [3 - ((4aR *, 6S *, 8aS *) - 2-amino-6-methyl4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia -1-azanaphthalen-8a-yl) -4fluorophenyl] -5-chloropyridin-2-carboxamide

ESI-MS m / z 435 [M ++ H]

Example 7

Chemical structure Compound name: N- [3 - ((4aR *, 6S *, 8aS *) - 2-amino-6-methyl4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia -1-azanaphthalen-8a-yl) -4fluorophenyl] -5-cyanopyridin-2-carboxamide

ESI-MS m / z 426 [M ++ H]

Example 8

Chemical structure Compound name: N- [3 - ((4aR *, 6S *, 8aS *) - 2-amino-6-methyl4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia -1-azanaphthalen-8a-yl) -4fluorophenyl] -5-trifluoromethylpyridin-2-carboxamide

ESI-MS m / z 469 [M ++ H]

Example 9

Chemical structure Compound name: N- [3 - ((4aR *, 6S *, 8aS *) - 2-amino-6-methyl4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia -1-azanaftalen-8a-il) -4fluorophenyl] -5-difluoromethoxypyrazin-2-carboxamide

ESI-MS m / z 468 [M ++ H]

Example 10

Chemical structure Compound name: N- [3 - ((4aR *, 6S *, 8aS *) - 2-amino-6-methyl4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia -1-azanaphthalen-8a-yl) -4fluorophenyl] -5-fluoromethoxypyrazin-2-carboxamide

ESI-MS m / z 450 [M ++ H]

Examples 11 to 15
The compounds of Examples 11 to 15 below were synthesized according to Example 2 using the compound of Preparation 7- (12) and the corresponding carboxylic acids, as shown in the following Table 3.
[Table 3-1]

Example 11

Chemical structure Compound name: N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-methoxymethyl4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia -1-azanaphthalen-8a-yl) -4-fluorophenyl] -5cianopyridin-2-carboxamide

1H-NMR (400MHz, CDCl3) δ (ppm): 1.45-1.53 (m, 1H), 1.80-1.93 (m, 1H), 2.58-2.67 (m, 1H), 2.94-3.07 (m, 2H), 3.43 (s, 3H), 3.43-3.57 (m, 2H), 3.81-3.92 (m, 2H), 4.14-4.21 (m, 1H), 7.02-7.11 (m, 1H), 7.35-7.41 (m, 1H) , 7.97-8.06 (m, 1H), 8.16-8.23 (m, 1H), 8.37-8.44 (m, 1H), 8,868.91 (m, 1H), 9.80 (sa, 1H).

ESI-MS m / z 456 [M ++ H]

Example 12

Chemical structure Compound name: N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-methoxymethyl4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia -1-azanaphthalen-8a-yl) -4-fluorophenyl] -5difluoromethylpyrazin-2-carboxamide

1H-NMR (400MHz, CDCl3) δ (ppm): 1.45-1.54 (m, 1H), 1.79-1.92 (m, 1H), 2.58-2.67 (m, 1H), 2.94-3.07 (m, 2H), 3.42 (s, 3H), 3.43-3.48 (m, 1H), 3.50-3.57 (m, 1H), 3.82-3.92 (m, 2H), 4.13-4.20 (m, 1H), 6.79 (t, J = 54.6Hz , 1H), 7.02-7.10 (m, 1H), 7.35-7.41 (m, 1H), 7.96-8.04 (m, 1H), 8.88-8.93 (m, 1H), 9.47-9.52 (m, 1H), 9.60 (sa, 1H).

ESI-MS m / z 482 [M ++ H]

Example 13

Chemical structure Compound name: N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-methoxymethyl4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia -1-azanaphthalen-8a-yl) -4-fluorophenyl] -5chloropyridin-2-carboxamide

ESI-MS m / z 465 [M ++ H]

[Table 3-2]

Example 14

Chemical structure Compound name: N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-methoxymethyl4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia -1-azanaftalen-8a-il) -4-fluorophenyl] -5fluoromethoxypyrazin-2-carboxamide

ESI-MS m / z 480 [M ++ H]

Example 15

Chemical structure Compound name: N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-methoxymethyl4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia -1-azanaftalen-8a-il) -4-fluorophenyl] -5difluoromethoxypyrazin-2-carboxamide

ESI-MS m / z 498 [M ++ H]

Examples 16 to 30
The compounds of Examples 16 to 30 were synthesized according to Example 2 using the corresponding carboxylic acids and corresponding aniline intermediates in the Preparation Examples, as shown in the following Table 4.
[Table 4-1] [Table 4-2]

Example 16

Compound name: N- [3 - ((4aS, 5S, 8aS) -2-amino-5-fluoro-4,4a, 5,6,8,8ahexahydro-7-oxa-3-thia-1-azanaphthalen- 8a-yl) -4-fluorophenyl] -5-cyanopyridin-2carboxamide

1H-NMR (400MHz, CDCl3) δ (ppm): 2.87 (dd, J = 4.0, 12.4Hz, 1H), 2.99-3.07 (m, 1H), 3.17 (dd, J = 2.8, 12.8Hz, 1H), 3.53 (ddd, J = 4.8, 10.4, 10.4Hz, 1H), 3.74 (dd, J = 2.4, 11.2Hz, 1H), 4.08 (dd, J = 2.0, 11.2Hz, 1H), 4.26 (dd, J = 5.6, 10.4Hz, 1H), 4.18-5.01 (m, 1H), 7.11 (dd, J = 8.8.11.6Hz, 1H), 7.42 (dd, J = 2.8, 6.8Hz, 1H), 7.97 (ddd, J = 2.8, 4.0, 8.4Hz, 1H), 8.20 (dd, J = 2.4, 8.0Hz, 1H), 8.41 (dd, J = 0.8, 8.0Hz, 1H), 8.88 (dd, J = 0.8, 2.0Hz, 1H), 9.81 (s, 1H).

ESI-MS m / z 430 [M ++ H]

Example 17

Compound name: N- [3 - ((4aS, 5S, 8aS) -2-amino-5-fluoro-4,4a, 5,6,8,8ahexahydro-7-oxa-3-thia-1-azanaphthalen- 8a-yl) -4-fluorophenyl] -5-difluoromethylpyrazin2-carboxamide

1H-NMR (400MHz, CDCl3) δ (ppm): 2.87 (dd, J = 4.0, 12.8Hz, 1H), 2.99-3.07 (m, 1H), 3.17 (dd, J = 3.2, 12.8Hz, 1H), 3.50-3.57 (m, 1H) 3.74 (dd, J = 2.4, 10.8Hz, 1H), 4.08 (dd, J = 2.0, 10.8Hz, 1H), 4.27 (dd, J = 5.6, 10.4Hz, 1H), 4.80-5.00 (m, 1H), 6.80 (t, J = 54.4Hz, 1H), 7.13 (dd, J = 8.8.11.6Hz, 1H), 7.43 (dd, J = 2.4, 6.4Hz, 1H), 7.95 -7.99 (m, 1H), 8.93 (s, 1H), 9.52 (s, 1H), 9.62 (s, 1H).

ESI-MS m / z 456 [M ++ H]

Example 18

Compound name: N- [3 - ((4aS, 5S, 8aS) -2-amino-5-fluoro-4,4a, 5,6,8,8ahexahydro-7-oxa-3-thia-1-azanaphthalen- 8a-yl) -4-fluorophenyl] -5-chloropyridin-2carboxamide

ESI-MS m / z 439 [M ++ H]

Example 19

Compound name: N- [3 - ((4aS, 5S, 8aS) -2-amino-5-fluoro-4,4a, 5,6,8,8ahexahydro-7-oxa-3-thia-1-azanaphthalen- 8a-yl) -4-fluorophenyl] -5trifluoromethylpyridin-2-carboxamide

ESI-MS m / z 473 [M ++ H]

Example 20

Compound name: N- [3 - ((4aS, 5S, 8aS) -2-amino-5-fluoro-4,4a, 5,6,8,8ahexahydro-7-oxa-3-thia-1-azanaphthalen- 8a-yl) -4-fluorophenyl] -5difluoromethoxypyridin-2-carboxamide

ESI-MS m / z 471 [M ++ H]

Example 21

Compound name: N- [3 - ((4aS, 5S, 8aS) -2-amino-5-fluoro-4,4a, 5,6,8,8ahexahydro-7-oxa-3-thia-1-azanaphthalen- 8a-yl) -4-fluorophenyl] -5fluoromethoxypyrazin-2-carboxamide

ESI-MS m / z 454 [M ++ H]

Example 22

Compound name: N- [3 - ((4aS, 5S, 8aS) -2-amino-5-fluoro-4,4a, 5,6,8,8ahexahydro-7-oxa-3-thia-1-azanaphthalen- 8a-yl) -4-fluorophenyl] -5difluoromethoxypyrazin-2-carboxamide

ESI-MS m / z 472 [M ++ H]

Example 23

Compound name: N- [3 - ((4aR *, 5S *, 8aS *) - 2-amino-5-methyl4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-il) -4-fluorophenyl] -5chloropyridin-2-carboxamide

ESI-MS m / z 435 [M ++ H]

[Table 4-3] [Table 4-4]

Example 24

Compound name: N- [3 - ((4aR *, 5S *, 8aS *) - 2-amino-5-methyl 4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia- 1-azanaphthalen-8a-yl) -4-fluorophenyl] -5cianopyridin-2-carboxamide

ESI-MS m / z 426 [M ++ H]

Example 25

image48 Compound name: N- [3 - ((4aR *, 5S *, 8aS *) - 2-amino-5-methyl4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-il) -4-fluorophenyl] -5difluoromethoxypyrazin-2-carboxamide

ESI-MS m / z 468 [M ++ H]

Example 26

Compound name: N- [3 - ((4aR *, 5R *, 8aS *) - 2-amino-5-methyl4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-il) -4-fluorophenyl] -5chloropyridin-2-carboxamide

ESI-MS m / z 435 [M ++ H]

Example 27

Compound name: N- [3 - ((4aR *, 5R *, 8aS *) - 2-amino-5-methyl4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-il) -4-fluorophenyl] -5cianopyridin-2-carboxamide

ESI-MS m / z 426 [M ++ H]

Example 28

Compound name: N- [3 - ((4aR *, 5R *, 8aS *) - 2-amino-5-methyl4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-il) -4-fluorophenyl] -5difluoromethoxypyrazin-2-carboxamide

ESI-MS m / z 468 [M ++ H]

Example 29

Compound name: N- [3 - ((4aR *, 5R *, 8aS *) - 2-amino-5-methyl4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-il) -4-fluorophenyl] -5difluoromethylpyrazin-2-carboxamide

ESI-MS m / z 452 [M ++ H]

Example 30

Compound name: N- [3 - ((4aS *, 5R *, 8aS *) - 2-amino-5-methoxy4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-il) -4-fluorophenyl] -5cianopyridin-2-carboxamide

ESI-MS m / z 442 [M ++ H]

Example 31
5 Synthesis of N- [3 - ((2R *, 4aR *, 8aS *) - 2-amino-4-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia- 1-azanaphthalen-8a-yl) -4fluorophenyl] -5-cyanopyridin-2-carboxamide image49
(1) Synthesis of (±) - ((2R *, 4aR *, 8aS *) - 8a- {5 - [(5-cyanopyridin-2-carbonyl) -amino] -2-fluorophenyl} -4-methyl-4 , 4a, 5,6,8,8ahexahydro-7-oxa-3-thia-1-azanaphthalen-2-yl) -carbonate of tert-butyl
10 PyBOP (357 mg) was added to a solution of the compound obtained in Example 11- (10) of preparation (100 mg), the compound obtained in Example 3- (2) of preparation (56 mg) and N, N -diisopropylethylamine (143 µl) in dichloromethane (5 ml), and the mixture was stirred at room temperature for five hours. The reaction solution was loaded directly to a silica gel and purified by silica gel column chromatography to obtain the title compound (100 mg).
ESI-MS; m / z 526 [M ++ H].
(2) Synthesis of (±) - ((2R *, 4aR *, 8aS *) - 8a- {5 - [(5-cyanopyridin-2-carbonyl-amino] -2-fluorophenyl} -4-methyl-4, 4a, 5,6,8,8a5 hexahydro-7-oxa-3-thia-1-azanaphthalen-2-yl) -carbonate of tert-butyl
The compound obtained in Example 31- (1) was purified by CHIRALPAK ™ IB (mobile phase: hexane: ethanol = 7: 3, flow rate: 10 ml / min.), And the fraction was collected with a retention time of 23 , 4 to 26.7 minutes to obtain the title compound. The same operation was repeated to obtain the title compound (20 mg;> 99% ee) from the crude material (100 mg).
10 ESI-MS; m / z 526 [M ++ H].
(3) Synthesis of N- [3 - ((2R *, 4aR *, 8aS *) - 2-amino-4-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3- thia-1-azanaftalen-8a-il) -4fluorophenyl] -5-cyanopyridin-2-carboxamide
TFA (1 ml) was added to a solution of the compound obtained in Example 31- (2) (20 mg) in chloroform (2 ml), and the mixture was stirred at room temperature for five hours. The reaction solution was neutralized with
15 aqueous saturated sodium bicarbonate. Chloroform was added to the mixture, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure to obtain the title compound (14 mg).
ESI-MS; m / z 426 [M ++ H].
Example 32
Synthesis of N- [3 - ((2R *, 4aR *, 8aS *) - 2-amino-4-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia- 1-azanaphthalen-8a-yl) -4fluorophenyl] -5-difluoromethylpyrazin-2-carboxamide image50
(1) Synthesis of (±) - ((2R *, 4aR *, 8aS *) - 8a- {5 - [(5-difluoromethylpyrazin-2-carbonyl) -amino] -2-fluoro-phenyl} -4-methyl4 , 4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-aza-naphthalen-2-yl) -carbonate of tert-butyl
The title compound (132 mg) was obtained from the compound obtained in Example 11- (10) of preparation (100 mg) and the compound obtained in Example 12- (5) of preparation (56 mg) according to the Example 31- (1).
ESI-MS; m / z 552 [M ++ H].
(2) Synthesis of (+1 - ((2R *, 4aR *, 8aS *) - 8a- {5 - [(5-difluoromethylpyrazin-2-carbonyl) -amino] -2-fluoro-phenyl} -4-methyl4 , 4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-2-yl) -carbonate of tert-butyl
The compound obtained in Example 32- (1) was purified by CHIRALPAK ™ IA (mobile phase: ethanol, flow rate: 10 ml / min.), And the fraction was collected with a retention time of 10.8 to 13, 5 minutes to obtain the title compound. The same operation was repeated to obtain the title compound (52 mg;> 99% ee) from the crude material (130 mg).
ESI-MS; m / z 552 [M ++ H].
35 (3) Synthesis of N- [3 - ((2R *, 4aR *, 8aS *) - 2-amino-4-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3 -tia-1-azanaftalen-8a-il) -4fluorophenyl] -5-difluoromethylpyrazin-2-carboxamide
TFA (1 ml) was added to a solution of the compound obtained in Example 32- (2) (52 mg) in chloroform (3 ml), and the mixture was stirred at room temperature for four hours. The reaction solution was neutralized with saturated aqueous sodium bicarbonate. Chloroform was added to the mixture, and the organic layer was separated. The layer
The organic was dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (42 mg).
ESI-MS; m / z 452 [M ++ H].
Examples 33 to 34
The compounds of Examples 33 to 34 were synthesized according to Example 2 using the corresponding carboxylic acids and corresponding aniline intermediates in the Preparation Examples, as shown in the following Table 5.
[Table 5]

Example 33

Chemical structure Compound name: N- [3 - ((4aR, 6R, 8aS) -2-amino-6-hydroxymethyl4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1- azanaftalen-8a-il) -4-fluorophenyl] -5chloropyridin-2-carboxamide

ESI-MS m / z 451 [M ++ H]

Example 34

Chemical structure Compound name: N- [3 - ((4aR, 6R, 8aS) -2-amino-6-hydroxymethyl4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1- azanaftalen-8a-il) -4-fluorophenyl] -5cianopyridin-2-carboxamide

ESI-MS m / z 442 [M ++ H]

Examples 35 to 43
5
The compounds of Examples 35 to 43 were synthesized according to Example 2 using the corresponding carboxylic acids and corresponding aniline intermediates in the Preparation Examples, as shown in the following Table 6.
10 [Table 6-1]

Example 35

Chemical structure Compound name: N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-trifluoromethyl4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia -1-azanaphthalen-8a-yl) -4-fluorophenyl] -5cianopyridin-2-carboxamide

1H-NMR (400MHz, CDCl3) δ (ppm): 1.69-1.73 (m, 1H), 2.12 (ddd, J = 2.4, 12.4, 24.8Hz, 1H), 2.67 (dd, J = 2.4, 12.4Hz, 1H ), 2.99-3.07 (m, 2H), 3.95 (d, J = 11.2Hz, 1H), 4.05-4.09 (m, 1H), 4.18 (d, J = 2.0, 11.2Hz, 1H), 7.09 (dd, J = 8.8, 11.6Hz, 1H), 7.40 (dd, J = 2.8, 6.4Hz, 1H), 8.00-8.05 (m, 1H), 8.21 (dd, J = 2.0, 8.0Hz, 1H), 8.42 (d , J = 8.0Hz, 1H), 8.90 (s, 1H), 9.81 (s, 1H).

Example 36

Chemical structure Compound name: N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-trifluoromethyl4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia -1-azanaftalen-8a-il) -4-fluorophenyl] -5difluoromethoxypyrazin-2-carboxamide

1H-NMR (400MHz, CDCl3) δ (ppm): 1.69-1.73 (m, 1H), 2.13 (ddd, J = 2.4, 12.0, 24.8Hz, 1H), 2.67 (dd, J = 2.4, 12.0Hz, 1H ), 2.98-3.07 (m, 2H), 3.98 (d, J = 10.8Hz, 1H), 4.04-4.11 (m, 1H), 4.17 (dd, J = 2.0, 12.8Hz, 1H), 7.02 (dd, J = 8.4, 11.6Hz, 1H), 7.38 (dd, J = 2.8, 6.8Hz, 1H), 7.51 (t, J = 71.2Hz, 1H), 7.91-7.95 (m, 1H), 8.27 (d, J = 1.2Hz, 1H), 9.01 (d, J-1.2Hz, 1H), 9.37 (s, 1H).

[Table 6-2] [Table 6-3]

Example 37

Chemical structure Compound name: N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-trifluoromethyl4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia -1-azanaphthalen-8a-yl) -4-fluorophenyl] -5fluoropyridin-2-carboxamide

ESI-MS m / z 473 [M ++ H]

Example 38

Chemical structure Compound name: N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-trifluoromethyl4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia -1-azanaphthalen-8a-yl) -4-fluorophenyl] pyridin-2-carboxamide

ESI-MS m / z 455 [M ++ H]

Example 39

Chemical structure Compound name: N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-trifluoromethyl4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia -1-azanaftalen-8a-il) -4-fluorophenyl] -5fluoromethoxypyrazin-2-carboxamide

ESI-MS m / z 504 [M ++ H]

Example 40

Chemical structure Compound name: N- [3 - ((4aR *, 6R *, BaS *) - 2-amino-6-trifluoromethyl4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia -1-azanaphthalen-8a-yl) -4-fluorophenyl] pyrimidin-4-carboxamide

ESI-MS m / z 456 [M ++ H]

Example 41

Chemical structure Compound name: N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-trifluoromethyl4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia -1-azanaphthalen-8a-yl) -4-fluorophenyl] 3,5-difluoropyridin-2-carboxamide

ESI-MS m / z 491 [M ++ H]

Example 42

Chemical structure Compound name: N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-trifluoromethyl4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia -1-azanaphthalen-8a-yl) -4-fluorophenyl] -5difluoromethoxypyridin-2-carboxamide

1H-NMR (400MHz, CDCl3) δ (ppm): 1.68-1.73 (m, 1H), 2.13 (ddd, J = 2.8, 12.4, 25.2Hz, 1H), 2.66 (dd, J = 2.8, 12.4Hz, 1H ), 2.98-3.03 (m, 1H), 3.06 (dd, J = 4.4, 12.4Hz, 1H), 3.97 (d, J = 10.8Hz, 1H), 4.04-4.13 (m, 1H), 4.18 (dd, J = 2.0, 10.8Hz, 1H), 6.65 (t, J = 71.6Hz, 1H), 7.03 (dd, J = 8.8, 12.0Hz, 1H), 7.38 (dd, J = 2.8, 7.2Hz, 1H), 7.65 (dd, J = 2.8, 8.8Hz, 1H), 7.97-8.00 (m, 1H), 8.28 (d, J = 8.8Hz, 1H), 8.43 (d, J = 2.4Hz, 1H), 9.75 (s , 1 HOUR).

[Table 6-4]

Example 43

Chemical structure Compound name: N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-trifluoromethyl4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia -1-azanaphthalen-8a-yl) -4-fluorophenyl] -5difluoromethylpyrazin-2-carboxamide

1H-NMR (400MHz, CDCl3) δ (ppm): 1.69-1.74 (m, 1H), 2.12 (ddd, J = 2.4, 12.0, 24.8Hz, 1H), 2.68 (dd, J = 2.8, 12.4Hz, 1H ), 2.99-3.08 (m, 2H), 3.95 (d, J = 11.2Hz, 1H), 4.05-4.11 (m, 1H), 3.18 (dd, J = 2.0, 10.8Hz, 1H), 6.80 (t, J = 54.4Hz, 1H), 7.09 (dd, J = 8.8, 12.0Hz, 1H), 7.41 (dd, J = 2.8, 7.2Hz, 1H), 7.97-8.01 (m, 1H), 8.91 (d, J = 0.8Hz, 1H), 9.51 (t, J = 0.8Hz, 1H), 9.60 (s, 1H).

Examples 44 to 48
The compounds of Examples 44 to 48 were synthesized according to Example 2 using the corresponding carboxylic acids and corresponding aniline intermediates in the Preparation Examples, as shown in the following Table 7.
[Table 7-1] [Table 7-2]

Example 44

Chemical structure Compound name: N- [3 - ((4aR, 6R, 8aS) -2-amino-6-fluoromethyl4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1- azanaftalen-8a-il) -4-fluorophenyl] -5cianopyridin-2-carboxamide

ESI-MS m / z 444 [M ++ H]

Example 45

Chemical structure Compound name: N- [3 - ((4aR, 6R, 8aS) -2-amino-6-fluoromethyl4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1- azanaftalen-8a-il) -4-fluorophenyl] -5chloropyridin-2-carboxamide

ESI-MS m / z 453 [M ++ H]

Example 46

Chemical structure Compound name: N- [3 - ((4aR, 6R, 8aS) -2-amino-6-fluoromethyl4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1- azanaftalen-8a-yl) -4-fluorophenyl] -5trifluoromethylpyridin-2-carboxamide

ESI-MS m / z 487 [M ++ H]

Example 47

Chemical structure Compound name: N- [3 - ((4aR, 6R, 8aS) -2-amino-6-fluoromethyl4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1- azanaftalen-8a-il) -4-fluorophenyl] -5fluoromethoxypyrazin-2-carboxamide

1H-NMR (400MHz, CDCl3) δ (ppm): 1.49-1.54 (m, 1H), 1.83-1.92 (m, 1H), 2.63 (dd, J = 2.4, 12.4Hz, 1H), 3.00-3.07 (m , 2H), 3.90 (d, J = 11.2Hz, 1H), 3.93-4.00 (m, 1H), 4.16 (dd, J = 1.6, 11.2Hz, 1H), 4.35-4.58 (m, 2H), 6.09 ( dd, J = 2.0, 3.6Hz, 1H), 6.21 (dd, J = 2.0, 4.0Hz, 1H), 7.06 (dd, J = 8.8, 12.0Hz, 1H), 7.35 (dd, J = 2.4, 6.4Hz , 1H), 7.97-8.01 (m, 1H), 8.27 (d, J = 0.8Hz, 1H), 9.06 (t, J = 0.8Hz, 1H), 9.45 (s, 1H).

Example 48

Chemical structure Compound name: N- [3 - ((4aR, 6R, 8aS) -2-amino-6-fluoromethyl4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1- azanaftalen-8a-il) -4-fluorophenyl] -5difluoromethylpyrazin-2-carboxamide

1H-NMR (400MHz, CDCl3) δ (ppm): 1.49-1.54 (m, 1H), 1.83-1.92 (m, 1H), 2.65 (dd, J = 2.8, 12.4Hz, 1H), 3.00-3.07 (m , 2H), 3.89 (d, J = 10.8Hz, 1H), 3.93-4.00 (m, 1H), 4.17 (dd, J = 2.0, 10.8Hz, 1H), 3.45-4.59 (m, 2H), 6.76 ( t, J = 54.8Hz, 1H), 7.08 (dd, J = 8.8, 12.0Hz, 1H), 7.40 (dd, J = 2.8, 6.4Hz, 1H), 7.97-8.01 (m, 1H), 8.91 (d , J = 1.2Hz, 1H), 9.51 (d, J = 1.2Hz, 1H), 9.60 (s, 1H).

Examples 49 to 58
The compounds of Examples 49 to 58 were synthesized according to Example 2 using the corresponding carboxylic acids and corresponding aniline intermediates in the Preparation Examples, as shown in the following Table 8.
[Table 8-1] [Table 8-2]

Example 49

Chemical structure Compound name: N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8ahexahydro-7-oxa-3-thia-1-azanaphthalen-8a- il) -4-fluorophenyl] -5-chloropyridin-2carboxamide

1H-NMR (400MHz, CDCl3) δ (ppm): 1.45 (dd, J = 2.0, 13.6Hz, 1H), 2.102.20 (m, 1H), 2.63 (dd, J = 2.8, 12.4Hz, 1H), 2.92-2.96 (m, 1H), 3.02 (dd, J = 4.4, 12.8Hz, 1H), 3.66-3.72 (m, 1H), 3.80 (d, J = 10.8Hz, 1H), 4.04-4.15 (m, 2H), 7.05 (dd, J = 8.8, 11.6Hz, 1H), 7.37 (dd, J = 2.8, 6.8Hz, 1H), 7.87 (dd, J = 2.0, 8.4Hz, 1H), 7.97-8.01 (m , 1H), 8.21 (d, J = 8.4Hz, 1H), 8.53 (d, J = 2.0Hz, 1H), 9.77 (s, 1H).

Example 50

Chemical structure Compound name: N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8ahexahydro-7-oxa-3-thia-1-azanaphthalen-8a- il) -4-fluorophenyl] -5-bromopyridin-2carboxamide

1H-NMR (400MHz, CDCl3) δ (ppm): 1.45 (d, J = 12.8Hz, 1H), 2.10-2.19 (m, 1H), 2.65 (dd, J = 2.4, 12.4Hz, 1H), 2.93- 2.97 (m, 1H), 3.03 (dd, J = 4.0, 12.0Hz, 1H), 3.69 (t, J = 12.0Hz, 1H), 3.79 (d, J = 10.8Hz, 1H), 4.05-4.14 (m , 2H), 7.07 (dd, J = 8.8, 12.0Hz, 1H), 7.36-7.39 (m, 1H), 7.98-8.05 (m, 2H). 8.16 (d, J = 8.0, 1H), 8.66 (s, 1H), 9.79 (s, 1H).

Example 51

Chemical structure Compound name: N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8ahexahydro-7-oxa-3-thia-1-azanaphthalen-8a- il) -4-fluorophenyl] -3.5-difluoropyridin2-carboxamide

1H-NMR (400MHz, CDCl3) δ (ppm): 1.45 (dt, J = 2.0, 13.6Hz, 1H). 2,052.19 (m, 1H). 2.64 (dd, J = 3.2, 12.4Hz, 1H), 2.91-2.97 (m, 1H), 3.02 (dd, J = 4.0, 12.0Hz, 1H), 3.65-3.72 (m, 1H), 3.78 (d, J = 10.8Hz, 1H), 4.03-4.15 (m, 2H), 7.06 (dd, J = 8.8, 12.0Hz, 1H), 7.24-7.27 (m, 1H), 7.36-7.41 (m, 1H), 8.05 -8.09 (m, 1H), 8.33 (d, J = 2.0Hz, 1H), 9.56 (s, 1H).

Example 52

Chemical structure Compound name: N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8ahexahydro-7-oxa-3-thia-1-azanaphthalen-8a- il) -4-fluorophenyl] -3.5-dichloropyridin2-carboxamide

1H-NMR (400MHz, CDCl3) δ (ppm): 1.43-1.47 (m, 1H), 2.08-2.19 (m, 1H), 2.64 (dd, J = 3.2, 12.4Hz, 1H), 2.92-2.97 (m , 1H), 3.01 (dd, J = 4.4, 12.4Hz, 1H), 3.65-3.71 (m, 1H), 3.76 (d, J = 11.2Hz, 1H), 4.03-4.11 (m, 2H), 7.07 ( dd, J = 9.2, 12.0Hz, 1H), 7.19 (dd, J = 2.8, 6.8Hz, 1H), 7.90 (d, J = 2.0Hz, 1H), 8.11-8.15 (m, 1H), 8.46 (d , J = 2.0Hz, 1H), 9.68 (s, 1H).

[Table 8-3] [Table 8-4]

Example 53

Chemical structure Compound name: N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8ahexahydro-7-oxa-3-thia-1-azanaphthalen-8a- il) -4-fluorophenyl] -5-fluoropyridin-2carboxamide

1H-NMR (400MHz, CDCl3) δ (ppm): 1.43-1.47 (m, 1H), 2.09-2.20 (m, 1H), 2.63 (dd, J = 2.8, 12.0Hz, 1H), 2.91-2.97 (m , 1H), 3.02 (dd, J = 4.0, 12.0Hz, 1H), 3.65-3.72 (m, 1H), 3.79 (d, J = 10.8Hz, 1H), 4.04-4.12 (m, 2H), 7.06 ( dd, J = 8.8, 11.6Hz, 1H), 7.3 (dd, J = 2.4, 6.4Hz, 1H), 7.59 (dt, J = 2.4, 8.4Hz, 1H), 7.99-8.03 (m, 1H), 8.31 (dd, J = 4.4, 8.4Hz, 1H), 8.44 (d, J = 2.8Hz, 1H), 9.76 (s, 1H).

Example 54

Chemical structure Compound name: N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8ahexahydro-7-oxa-3-thia-1-azanaphthalen-8a- il) -4-fluorophenyl] -3.5 dibromopyridin-2-carboxamide

ESI-MS m / z 545 [M ++ H]

Example 55

Chemical structure Compound name: N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8ahexahydro-7-oxa-3-thia-1-azanaphthalen-8a- il) -4-fluorophenyl] -5trifluoromethylpyridin-2-carboxamide

1H-NMR (400MHz, CDCl3) δ (ppm): 1.43-1.47 (m, 1H), 2.10-2.19 (m, 1H), 2.65 (dd, J = 3.2, 12.4Hz, 1H), 2.92-2.97 ( m, 1H), 3.03 (dd, J = 4.0, 12.0Hz, 1H), 3.66-3.72 (m, 1H), 3.79 (d, J = 11.2Hz, 1H), 4.05-4.12 (m, 2H), 7.08 (dd, J = 8.8, 12.0Hz, 1H), 7.39 (dd, J = 2.8, 6.4Hz, 1H), 8.00-8.04 (m, 1H), 8.16 (dd, J = 1.6, 8.4Hz, 1H), 8.42 (d, J = 8.0Hz, 1H), 8.88 (t, J = 0.8Hz, 1H), 9.89 (s, 1H).

Example 56

Chemical structure Compound name: N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8ahexahydro-7-oxa-3-thia-1-azanaphthalen-8a- il) -4-fluorophenyl] -5difluoromethylpyridin-2-carboxamide

1H-NMR (400MHz, CDCl3) δ (ppm): 1.43-1.47 (m, 1H), 2.09-2.21 (m, 1H). 2.64 (dd, J = 2.8, 12.0Hz, 1H), 2.92-2.98 (m, 1H), 3.02 (dd, J = 8.0, 12.4Hz, 1H), 3.66-3.72 (m, 1H), 3.81 (d, J = 10.8Hz, 1H), 4.05-4.15 (m, 2H), 6.81 (t, J = 55.6Hz, 1H), 7.05 (dd, J = 9.2, 12.0Hz, 1H), 8.40 (dd, J = 2.8 , 6.8Hz, 1H), 7.98-8.06 (m, 2H), 8.36 (d, J = 8.4Hz, 1H), 8.73 (s, 1H), 9.90 (s, 1H).

[Table 8-5]

Example 57

Chemical structure Compound name: N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,8,8a-hexahydro7-oxa-3-thia-1-azanaphthalen-8a-yl) -4-fluorophenyl] -5-difluoromethylpyrazin-2carboxamide

1H-NMR (400MHz, CDCl3) δ (ppm): 1.44-1.48 (m, 1H), 2.10-2.19 (m, 1H), 2.65 (dd, J = 2.8, 12.0Hz, 1H), 2.93-3.04 (m , 2H), 3.66-3.72 (m, 1H), 3.80 (d, J = 11.2Hz, 1H), 4.04-4.15 (m, 2H), 6.79 (t, J = 54.4Hz.1H). 7.08 (dd, J = 8.8, 12.0Hz, 1H), 7.40 (dd, J = 2.8, 6.4Hz, 1H), 7.97-8.01 (m, 1H), 8.90 (d, J = 0.8Hz, 1H), 9.50 (s, 1H), 9.60 (s, 1H).

Example 58

Chemical structure Compound name: N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8ahexahydro-7-oxa-3-thia-1-azanaphthalen-8a- il) -4-fluorophenyl] -5difluoromethoxypyridin-2-carboxamide

1H-NMR (400MHz, CDCl3) δ (ppm): 1.43-1.47 (m, 1H), 2.05-2.20 (m, 1H), 2.63 (dd, J = 2.8, 12.0Hz, 1H), 2.91-2.97 (m , 1H), 3.03 (dd, J = 4.0, 12.4Hz, 1H), 3.65-3.72 (m, 1H), 8.79 (d, J = 11.2Hz, 1H), 4.04-4.13 (m, 2H), 6.65 ( t, J = 72.0Hz, 1H), 7.07 (dd, J = 8.8, 12.0Hz, 1H). 7.36 (dd, J = 3.2, 7.2Hz, 1H), 7.66 (dd, J = 3.2, 8.8Hz, 1H), 8.00-8.04 (m, 1H), 8.31 (d, J = 9.2Hz, 1H), 8.46 (d, J = 2.4Hz, 1H), 9.80 (s, 1H).

Example 59
Synthesis of (±) - (4aR *, 6R *, 8aS *) - 8a- [2-fluoro-5- (2-fluoropyridin-3-yl) phenyl] -6-trifluoromethyl-4,4a, 5,6, 8,8a-hexahydro-7-oxa3-thia-1-azanaphthalen-2-ylamine
[Formula 53] image51
10 2-Fluoropyridin-3-boronic acid (63.9 mg), tetrakis (triphenylphosphine) palladium (26.2 mg) and a 1 N solution of sodium carbonate (453 µl) were added to a solution of (±) -N, N-di (tert-butyloxycarbonyl) - [(4aR *, 6R *, 8aS *) - 8a- (5-bromo2-fluorophenyl) -6-trifluoromethyl-4,4a, 5,6,8,8a- hexahydro-7-oxa-3-thia-1-azanaphthalen-2-yl] amine (138 mg) in DMF (9.9 ml), and the mixture was stirred under a nitrogen atmosphere at 85 ° C for seven hours. The reaction solution was cooled to room temperature and then diluted with ethyl acetate. The organic layer was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Dichloromethane (4.0 ml) and TFA (1.0 ml) were added to the residue, and the mixture was stirred at temperature
5 room for four hours. When the reaction was terminated, the reaction solution was diluted with dichloromethane, and ice was added, followed by neutralization with a solution of sodium bicarbonate. The aqueous layer was extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography. The resulting white solid was washed with diethyl ether to obtain the title compound (14.0 mg).
10 1H-NMR (400 MHz, CDCl3) δ (ppm): 1.68-1.72 (m, 1H), 2.12 (ddd, J = 2.8, 12.0, 24.8 Hz, 1H ), 2.68 (dd, J = 2.4, 12.4 Hz, 1H), 2.99-3.08 (m, 2H), 3.96 (d, J = 11.6 Hz, 1H) , 4.06-4.11 (m, 1H), 4.20 (dd, J = 2.0, 11.2 Hz, 1H), 7.15 (dd, J = 8.8, 12.4 Hz , 1H), 7.25-7.30 (m, 1H), 7.50-7.54 (m, 2H), 7.83 (ddd, J = 1.6, 7.2, 9.2 Hz , 1H), 8.19-8.21 (m, 1H).
Example 60
Synthesis of (4aR, 6R, 8aS) -8a- [2-fluoro-5- (2-fluoropyridin-3-yl) phenyl] -6-fluoromethyl-4,4a, 5,6,8,8a-hexahydro-7 -oxa-3-tia-115 azanaftalen-2-ylamine
[Formula 54] image52
2-fluoropyridin-3-boronic acid (51.1 mg), tetrakis (triphenylphosphine) palladium (19.1 mg) and a 1 N solution of sodium carbonate (363 µl) were added to a solution of N, N- di (tert-butyloxycarbonyl) - [(4aR, 6R, 8aS) -8a- (5-bromo-220 fluorophenyl) -6-fluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3 -tia-1-azanaftalen-2-yl] amine (95 mg) in DMF (6.79 ml). After replacing with nitrogen, the mixture was stirred at 85 ° C for two hours. After cooling to room temperature, the mixture was diluted with water. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography. The intermediate
The resulting was dissolved in dichloromethane (4.0 ml). TFA (1.0 ml) was added, and the mixture was stirred at room temperature for three hours. Ice was added to the reaction mixture, followed by neutralization with a solution of sodium bicarbonate. The aqueous layer was extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (59.0 mg).
1 H-NMR (400 MHz, CDCl3) δ (ppm): 1.48-1.53 (m, 1H), 1.82-1.92 (m, 1H), 2.63-2.66 (m , 1H), 2.98-3.07 (m, 2H), 3.89 (d, J = 10.8 Hz, 1H), 3.93-4.01 (m, 1H), 4.17- 4.20 (m, 1H), 4.35-4.58 (m, 2H), 7.14 (dd, J = 8.0, 12.0 Hz, 1H), 7.257.22 (m, 1H) , 7.48-7.55 (m, 2H), 7.78-7.83 (m, 1H), 8.16-8.18 (m, 1H).
Example 61
Synthesis of (±) - (4aR *, 8aS *) - 8a- [2-fluoro-5- (2-fluoropyridin-3-yl) phenyl] -4,4a, 5,6,8,8a-hexahydro-7 -oxa-3-tia-135 azanaftalen-2-ylamine
[Formula 55] image53
2-fluoropyridin-3-boronic acid (25.6 mg), tetrakis (triphenylphosphine) palladium (10.5 mg) and a 1 N solution of sodium carbonate (182 µl) were added to a solution of (±) - N-benzoyl-N- (tert-butyloxycarbonyl) - [(4aR *, 8aS *) - 8a- (540 bromo-2-fluorophenyl) -4.4a, 5,6,8,8a-hexahydro-7-oxa- 3-thia-1-azanaphthalen-2-yl] amine (50 mg) in DMF (5.0 ml). After replacing with nitrogen, the mixture was stirred at 90 ° C for six hours. The reaction solution was cooled to room temperature and diluted with water. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel NH-chromatography to obtain the compound.
45 of the titer (12.7 mg).
1H-NMR (400 MHz, CDCl3) δ (ppm): 1.43-1.47 (m, 1H), 2.08-2.20 (m, 1H), 2.66 (dd, J = 2, 8, 12.0 Hz, 1H), 2.90-2.96 (m, 1H), 3.01 (dd, J = 4.0, 12.4 Hz, 1H), 3.69 (dt, J = 2.8, 12.4 Hz, 1H), 3.79 (d, J = 11.2 Hz, 1H), 4.07-4.13 (m, 2H), 4.60 (sa, 2H) , 7.14 (dd, J = 8.4, 12.0 Hz, 1H), 7.25-7.28 (m, 1H), 7.48-7.55 (m, 2H), 7.81 -7.86 (m, 1H), 8.18-8.20 (m, 1H).
Examples 62 to 63
The compounds of Examples 62 to 63 were synthesized according to Example 61 using the corresponding boronic acids, as shown in the following Table 9.
[Table 9]

Example 62

Chemical structure Compound name: (±) - (4aR *, 8aS *) - 8a- (2-fluoro-5-pyrimidin-5-ylphenyl) 4,4a, 5,6,8,8a-hexahydro-7-oxa -3-thia-1-azanaphthalen-2-ylamine

image54

ESI-MS m / z 345 [M ++ H]

Example 63

Chemical structure Compound name: (±) - (4aR *, 8aS *) - 8a- [5- (5-chloropyridin-3-yl) -2fluorophenyl] -4,4a, 5,6,8,8a-hexahydro- 7-oxa-3-thia-1-azanaphthalen-2-ylamine

ESI-MS m / z 378 [M * + H]

Example 64 Synthesis of N- [5 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-8a -il) thiophen-3-yl] -5cianopyridin-2-carboxamide [Formula 56] image55
15 Sequentially added 5-cyanopyridin-2-carboxylic acid (19.0 mg), diisopropylethylamine (50.7 µl) and PyBOP (83.5 mg) to a solution of (+) - N, N-di (tert) -butyloxycarbonyl) - [(4aR *, 8aS *) - 8a- (4-aminothiophene-2-yl) -4,4a, 5,6,8,8ahexahydro-7-oxa-3-thia-1-azanaftalen-2 -il] amine (50 mg) in dichloromethane (5.0 ml) in an ice bath. The mixture was returned to room temperature and stirred overnight. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography. The resulting intermediate was dissolved in
Dichloromethane (4.0 ml), and TFA (1.0 ml) was added. After stirring at room temperature for four hours, ice was added to terminate the reaction. The mixture was neutralized with a solution of sodium bicarbonate, and the aqueous layer was neutralized with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (33.9 mg).
25 ESI-MS m / z 400 [M ++ H]
Example 65
Synthesis of (±) - (4aR *, 8aR *) - 8a- [4- (2-fluoropyridin-3-yl) -thiophene-2-yl] -4,4a, 5,6,8,8a-hexahydro- 7-oxa-3-thia-1-azanaphthalen-2-amine
[Formula 57] image56
5
2-fluoropyridin-3-boronic acid (26.9 mg), tetrakis (triphenylphosphine) palladium (11.0 mg) and a 1 N solution of sodium carbonate (191 µl) were added sequentially to a solution of (±) -N, N-di- (tert-butyloxycarbonyl) - [(4aR *, 8aS *) 8a- (4-bromothiophene-2-yl) -4,4a, 5,6,8,8a-hexahydro-7-oxa -3-thia-1-azanaphthalen-2-yl] amine obtained in Example 19- (3) of preparation (51.0 mg) in DMF (2.0 ml). After replacing with nitrogen, the mixture was stirred at 80 ° C for five 10 hours. The reaction solution was returned to room temperature and diluted with water. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain an intermediate. The resulting intermediate was dissolved in dichloromethane (5.0 ml). TFA (2.0 ml) was added, and the mixture was stirred at room temperature for three hours. Ice was added to the
Mix, followed by neutralization with a solution of sodium bicarbonate. The aqueous layer was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel NH-chromatography to obtain the title compound (22.0 mg).
ESI-MS m / z 350 [M ++ H]
20 Example 66
Synthesis of (4aR, 6R, 8aS) -8a- [2-fluoro-5- (2-fluoropyridin-3-yl) phenyl] -6-benzyloxymethyl-4,4a, 5,6,8,8a-hexahydro-7 -oxa-3tia-1-azanaphthalen-2-ylamine
[Formula 58] image57
25 2-Fluoropyridin-3-boronic acid (44.0 mg), tetrakis (triphenylphosphine) palladium (18.0 mg) and a 1 N solution of sodium carbonate (312 µl) were added to a solution of N, N -di- (tert-butyloxycarbonyl) - [(4aR, 6R, 8aS) -8a- (5-bromo-2fluorophenyl) -6-benzyloxymethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa- 3-thia-1-azanaftalen-2-yl] amine (95 mg) in DMF (6.79 ml). After replacing with nitrogen, the mixture was stirred at 85 ° C for seven hours. After cooling to room temperature, the mixture was diluted with water. The aqueous layer was extracted with ethyl acetate, and the layer
30 organic washed with water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography. The resulting intermediate was dissolved in dichloromethane (4.0 ml). TFA (1.0 ml) was added, and the mixture was stirred at room temperature for three hours. Ice was added to the reaction mixture, followed by neutralization with a solution of sodium bicarbonate. The aqueous layer was extracted with chloroform, and the organic layer was dried over sulfate.
35 anhydrous magnesium. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (23.0 mg).
ESI-MS m / z 482 [M ++ H]
Example 67
Synthesis of (±) -N- [7 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen- 8a-yl) -2,2difluorobenzo [1,3] dioxol-5-yl] -5-cyanopyridin-2-carboxamide
[Formula 59] image58
5 5-Cyanopyridin-2-carboxylic acid (4.0 mg), diisopropylethylamine (11.5 µl) and PyBOP (17.6 mg) were added to a solution of (±) - [(4aR *, 8aS *) -8a- (6-amino-2,2-difluorobenzo [1,3] dioxol-4-yl) -4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1azanaftalen-2 -yl] tert-butyl carbamate (10 mg) in dichloromethane (2.0 ml) in an ice bath. The mixture was heated to room temperature and stirred for four hours. The solvent was evaporated under reduced pressure, and the residue was purified by NH-pTLC to obtain an intermediate. The resulting intermediate was dissolved in
Dichloromethane (3.0 ml), and TFA (1.0 ml) was added. After stirring at room temperature for four hours, the reaction solution was diluted with water and neutralized with a solution of sodium bicarbonate. The aqueous layer was extracted with dichloromethane, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by NH-pTLC to obtain the title compound.
1H-NMR (400 MHz, CDCl3) δ (ppm): 1.51-1.53 (m, 1H), 2.15 (ddd, J = 5.2, 13.2, 26.0 Hz, 1H) , 2.71 (dd, J = 2.8, 12.4
15 Hz, 1H), 2.86-2.90 (m, 1H), 3.07 (dd, J = 4.4, 12.4 Hz, 1H), 3.68-3.73 (m, 1H ), 3.85-3.91 (m, 2H), 4.11-4.15 (m, 1H), 7.03 (d, J = 2.0 Hz, 1H), 8.07 (d, J = 2.0 Hz, 1H), 8.21 (dd, J = 2.0, 8.0 Hz, 1H), 8.41 (dd, J = 0.8, 8.0 Hz, 1H), 8.92 (dd, J = 0.8, 2.0 Hz, 1H), 9.94 (sa, 1H).
Examples 68 to 73
The compounds of Examples 68 to 73 were synthesized according to Example 2 using carboxylic acids
20 and the corresponding aniline intermediates in the Preparation Examples, as shown in the following Table 10.
[Table 10-1] [Table 10-2]

Example 68

Chemical structure Compound name: N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro7-oxa-3-thia-1-azanaphthalen-8a- il) -4-fluorophenyl] -5- (2-methoxyethoxy) -pyrazin-2-carboxamide

1H-NMR (400MHz, CDCl3) δ (ppm): 1.40-1.50 (m, 1H), 2.01-2.21 (m, 1H), 2.59-2.68 (m, 1H), 2.88-2.98 (m, 1H), 2.98 -3.06 (m, 1H), 3.46 (s, 3H), 3,633.73 (m, 1H), 3.73-3.84 (m, 3H), 4.01-4.12 (m, 2H), 4.55-4.65 (m, 2H) , 7.027.11 (m, 1H), 7.29-7.35 (m, 1H), 7.98-8.06 (m, 1H), 8.19-8.24 (m, 1H), 8.969.01 (m, 1H), 9.46 (sa, 1 HOUR).

ESI-MS m / z 462 [M ++ H]

Example 69

Chemical structure Compound name: N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro7-oxa-3-thia-1-azanaphthalen-8a- il) -4-fluorophenyl] -2-methylthiazol-4-carboxamide

1H-NMR (400MHz, CDCl3) δ (ppm): 1.39-1.50 (m, 1H), 2.06-2.21 (m, 1H), 2.59-2.67 (m, 1H), 2.76 (s, 3H), 2.89-2.97 (m, 1H), 2.98-3.07 (m, 1H), 3,623.73 (m, 1H), 3.73-3.81 (m, 1H), 4.01-4.13 (m, 2H), 7.02-7.10 (m, 1H) , 7,287.34 (m, 1H), 7.93-7.99 (m, 1H), 8.04 (s, 1H), 9.17 (sa, 1H).

ESI-MS m / z 407 [M ++ H]

Example 70

Chemical structure Compound name: N- [3 - ((4aR *, 5R *, 8aS *) Compound name: N- [3 ((4aR *, 5R *, 8aS *) - 2-amino-5-methyl- 4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1azanaftalen-8a-yl) -4-fluorophenyl] -2,5-dimethylfuran-3-carboxamide

1H-NMR (400MHz, CDCl3) δ (ppm): 0.94 (d, J = 6.8Hz, 3H), 2.21-2.27 (m, 1H), 2.28 (s, 3H), 2.58 (s, 3H), 2.61- 2.68 (m, 1H), 2.93-2.96 (m, 2H), 3.25-3.36 (m, 1H), 3.85-3.92 (m, 1H), 3.95-4.07 (m, 2H), 6.21 (sa, 1H), 7.03-7.11 (m, 2H), 7.58-7.63 (m, 1H).

ESI-MS m / z 418 [M ++ H]

Example 71

Chemical structure Compound name: N- [3 - ((4aR *, 5R *, 8aS *) - 2-amino-5-methyl-4,4a, 5,6,8,8ahexahydro-7-oxa-3-thia -1-azanaphthalen-8a-yl) -4-fluorophenyl-4-methyl [1,2,3] thiadiazol-5-carboxamide

1H-NMR (400MHz, CDCl3) δ (ppm): 0.91 (d, J = 6.4Hz, 3H), 2.07-2.20 (m, 1H), 2.44-2.52 (m, 1H), 2.78-2.86 (m, 1H ), 2.86-2.93 (m, 1H), 2.96 (s, 3H), 3.223.31 (m, 1H), 3.66-3.74 (m, 1H), 3.84-3.91 (m, 1H), 4.02-4.08 (m , 1H), 7.057.12 (m, 1H), 7.14-7.19 (m, 1H), 7.91 (sa, 1H).

ESI-MS m / z 422 [M ++ H]

[Table 10-3]

Example 72

Chemical structure Compound name: N- [3 - ((4aR *, 5R *, 8aS *) - 2-amino-5-methyl-4,4a, 5,6-tetrahydro-7-oxa-3-thia-1-azanaphthalen -8a-yl) -4-fluorophenyl] -3-piperidin-1ylpropionamide

1H-NMR (400MHz, CDCl3) δ (ppm): 0.92 (d, J = 6 8Hz, 3H), 1.56-1.86 (m, 6H), 2.102.23 (m, 1H), 2.42-2.73 (m, 9H ), 2.84-2.96 (m, 2H), 3.24-3.36 (m, 1H), 3.834.01 (m, 2H), 4.06-4.13 (m, 1H), 6.9 6-7.12 (m, 2H), 7.90- 8.01 (m, 1H), 11.5 (sa, 1H).

ESI-MS m / z 435 [M ++ H]

Example 73

Chemical structure Compound name: N- [3 - ((4aR *, 5R *, 8aS *) - 2-amino-5-methyl-4,4a, 5,6-tetrahydro-7-oxa-3-thia-1-azanaphthalen -8a-yl) -4-fluorophenyl] -2-methylxazol-4carboxa measures

1H-NMR (400MHz, CDCl3) δ (ppm): 0.91 (d, J = 6. 8Hz, 3H), 2.11-2.27 (m, 1H), 2.42-2.50 (m, 1H), 2.5 0-2.57 (m, 3H), 2.80-2.94 (m, 2H), 3.23-3.34 (m, 1 H), 3.72-3.81 (m, 1H), 3.89-3.97 (m, 1H), 4.05-4.1 2 (m, 1H), 6.99-7.08 (m, 1H), 7.257.32 (m, 1H), 7.8 9-7.96 (m, 1H), 8.14-8.19 (m, 1H), 8.65 (sa, 1H).

ESI-MS m / z 405 [M ++ H]

Example 74
Synthesis of (4aR, 6R, 8aS) -8a- [2-fluoro-5- (2H-pyrazol-3-yl) phenyl] -6-methoxymethyl-4,4a, 5,6,8,8a-hexahydro-7 -oxa-3-tia-1azanaftalen-2-il] amine
[Formula 60] image59
(1) Synthesis of [(4aR, 6R, 8aS) -8a- (5-bromo-2-fluorophenyl) -6-methoxymethyl-4,4a, 5,6,8,8a-hexahydropyran [3,4d] [1 , 3] thiazin-2-yl] di-tert-butyl imidodicarbonate
The title compound was synthesized from the compound obtained in Example 7- (4) of preparation according to Example 16 (1) - (3) of preparation.
ESI-MS; m / z 611 [M ++ Na].
(2) Synthesis of [(4aR, 6R, 8aS) -8a- (5-acetyl-2-fluorophenyl) -6-methoxymethyl-4,4a, 5,6,8,8a-hexahydropyran [3,4-d] [1,3] thiazin2-yl] di-tert-butyl imidodicarbonate
The compound obtained in Example 74- (1) (2.73 g) was dissolved in 1,4-dioxane (40 ml), 1-ethoxyvinyltri-n-butyltin (2.42 ml), cesium fluoride were added sequentially (1.55 g) and bis (tri-t-butylphosphine) palladium (118 mg) to the solution, and the mixture was stirred under a nitrogen atmosphere at 100 ° C. After 1.5 hours, the reaction solution was allowed to cool. The reaction mixture was filtered through celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. Ethyl acetate and 1 N KHSO4 were added to the residue, and the organic layer was separated. The organic layer was washed sequentially with 1 N KHSO4, with a solution of sodium bicarbonate and with brine. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel chromatography to obtain {(4aR, 6R, 8aS) -8a- [5- (1-ethoxyvinyl) -2-fluorophenyl] -6-methoxymethyl-4,4a, 5,6,8 , 8a-hexahydropyran [3,4-d] [1,3] thiazin2-yl} di-tert-butyl imidodicarbonate (1.91 g). 1.5 g of 1.91 g of the resulting compound was dissolved in THF (10 ml). Then, 2N hydrochloric acid (3.5 ml) was added, and the mixture was stirred at room temperature. After one hour, ethyl acetate was added to the reaction solution, and the mixture was washed sequentially with a solution of sodium bicarbonate and with brine. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel chromatography to obtain the title compound (1.2 g).
ESI-MS; m / z 575 [M ++ Na].
(3) Synthesis of {(4aR, 6R, 8aS) -8a- [2-fluoro-5- (2H-pyrazol-3-yl) phenyl] -6-methoxymethyl-4,4a, 5,6,8,8a -hexahydro-7-oxa-3-thia1-azanaphthalen-2-yl} carbamate.
The compound obtained in Example 74- (2) (207 mg) was dissolved in N, N-dimethylformamide dimethyl acetal (2.3 ml), and then the solution was stirred under a nitrogen atmosphere at 110 ° C. After about 14 hours, the reaction solution was allowed to cool and then concentrated under reduced pressure. Ethanol (3 ml) was added to the residue, and hydrazine hydrate (78 µl) was then added, followed by stirring at room temperature. After about three days, the reaction solution was concentrated under reduced pressure. Ethyl acetate and a sodium bicarbonate solution were added to the residue, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel chromatography to obtain the title compound (38 mg).
ESI-MS; m / z 477 [M ++ 1].
(4) Synthesis of (4aR, 6R, 8aS) -8a- [2-fluoro-5- (2H-pyrazol-3-yl) phenyl] -6-methoxymethyl-4,4a, 5,6,8,8a- hexahydro-7-oxa-3-thia1-azanaphthalen-2-yl] amine
The compound obtained in Example 74- (3) (38 mg) was dissolved in dichloromethane (2 ml), and then trifluoroacetic acid (0.4 ml) was added, followed by stirring at room temperature. After three hours, the reaction solution was concentrated under reduced pressure. Chloroform and a solution of sodium bicarbonate were added to the residue, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography to obtain the title compound (18 mg).
ESI-MS; m / z 377 [M ++ 1]
Example 75
Synthesis of (4aR, 6R, 8aS) -8a- [2-fluoro-5- (2H-pyrazol-3-yl) phenyl] -6-methoxymethyl-4,4a, 5,6,8,8a-hexahydro-7 -oxa-3-tia-1azanaftalen-2-il] amine image60
The title compound was synthesized according to Example 74 using N, N-dimethylacetamide dimethyl acetal instead of N, N-dimethylformamide dimethyl acetal.
ESI-MS; m / z 391 [M ++ 1].
Example 76
Synthesis of (4aR, 6R, 8aS) -8a- [2-fluoro-5- (2-fluoropyridin-3-yl) phenyl] -6-methoxymethyl-4,4a, 5,6,8,8a-hexahydro-7 -oxa-3-tia15 1-azanaftalen-2-il] amine image61
(1) Synthesis of [(4aR, 6R, 8aS) -8a- [2-fluoro-5- (2-fluoropyridin-3-yl) phenyl] -6-methoxymethyl-4,4a, 5,6,8,8ahexahydropyran [3,4-d] [1,3] thiazin-2-yl] di-tert-butyl imidodicarbonate
The compound obtained in Example 74- (1) (1.33 g) was dissolved in THF (28 ml). 2-fluoropyridin-3 acid was added
Boronic (955 mg), potassium fluoride (558 mg), Pd2DBA3 (200 mg) and Pd (t-Bu3P) 2 (220 mg) to the solution, and the mixture was stirred under a nitrogen atmosphere at room temperature all the night. The reaction solution was diluted with ethyl acetate and filtered through NH silica gel. The filtrate was washed further with a mixture of ethyl acetate: heptane = 4: 1. The filtrate was concentrated under reduced pressure to obtain a residue. The residue was subjected to silica gel chromatography to obtain the title compound (547 mg).
ESI-MS; m / z 628 [M ++ Na].
(2) Synthesis of (4aR, 6R, 8aS) -8a- [2-fluoro-5- (2-fluoropyridin-3-yl) phenyl] -6-methoxymethyl-4,4a, 5,6,8,8a- hexahydro-7-oxa-3tia-1-azanaphthalen-2-yl] amine
The compound obtained in Example 76- (1) (67 mg) was dissolved in dichloromethane (2 ml), and then TFA (0.5 ml) was added. After two hours, the reaction solution was concentrated under reduced pressure. They were added
30 chloroform, a 1 N solution of sodium hydroxide and a solution of sodium bicarbonate to the residue, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated. The residue was subjected to silica gel chromatography to obtain the title compound (30 mg).
ESI-MS; m / z 406 [M ++ 1].
Example 77
Synthesis of (4aR, 6R, 8aS) -8a- [2-fluoro-5- (3-fluoropyridin-4-yl) phenyl-6-methoxymethyl-4,4a, 5,6,8,8a-hexahydro-7- oxa-3-tia-1azanaftalen-2-yl] amine image62
The title compound was synthesized according to Example 76. ESI-MS; m / z 406 [M ++ 1].
Example 78
Synthesis of (4aR, 6R, 8aS) -8a- [2-fluoro-5- (2-methoxypyridin-3-yl) phenyl] -6-methoxymethyl-4,4a, 5,6,8,8a-hexahydro-7 -oxa-3-tia10 1-azanaftalen-2-yl] amine
[Formula 64] image63
(1) Synthesis of {(4aR, 6R, 8aS) -8a- [2-fluoro-5- (2-methoxypyridin-3-yl) phenyl] -6-methoxymethyl-4,4a, 5,6,8,8a t-butyl hexahydro-7-oxa3-thia-1-azanaphthalen-2-yl} carbamate
Methanol (1 ml) and a 28% sodium methoxide solution - methanol (1 ml) were added to the compound synthesized in Example 76- (1) (164 mg), followed by stirring at 50 ° C. After three hours and 30 minutes, the reaction solution was allowed to cool. Ethyl acetate and a saturated solution of ammonium chloride were added to the reaction solution, and the organic layer was separated. The organic layer was washed with brine. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated to
20 reduced pressure. The residue was subjected to silica gel chromatography to obtain the title compound (114 mg).
ESI-MS; m / z 540 [M ++ Na].
(2) Synthesis of {(4aR, 6R, 8aS) -8a- [2-fluoro-5- (2-methoxypyridin-3-yl) phenyl] -6-methoxymethyl-4,4a, 5,6,8,8a -hexahydro-7-oxa3-thia-1-azanaphthalen-2-yl} amine
The compound obtained in Example 78- (1) (114 mg) was dissolved in dichloromethane (3 ml), and then TFA (1 ml) was added, followed by stirring at room temperature. After three hours, the reaction solution was concentrated under reduced pressure. Chloroform and a solution of sodium bicarbonate were added to the residue, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography.
30 to obtain the title compound (61 mg).
ESI-MS; m / z 418 [M ++ 1].
Example 79
Synthesis of (4aR, 6R, 8aS) -8a- [2-fluoro-5-pyridazin-3-ylphenyl] -6-methoxymethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3- tia-1azanaftalen-2-il] amine image64
(1) Synthesis of [(4aR, 6R, 8aS) -8a- (2-fluoro-5-pyridazin-3-ylphenyl) -6-methoxymethyl-4,4a, 5,6,8,8a-hexahydropyran [3, 4d] [1,3] thiazin-2-yl] di-tert-butyl imidodicarbonate
The compound synthesized in Example 76- (1) (229 mg) was dissolved in 1,4-dioxane (4 ml). They were added
5 sequentially 3- (tributylstannyl) pyridazine (215 mg), cesium fluoride (130 mg) and bis (tri-t-butylphosphine) palladium (10 mg) to the solution, and the mixture was stirred under a nitrogen atmosphere at 100 ° C . After two hours, the reaction solution was allowed to cool. The reaction mixture was filtered through celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel chromatography to obtain the title compound (116 mg).
10 ESI-MS; m / z 611 [M ++ Na].
(2) Synthesis of (4aR, 6R, 8aS) -8a- [2-fluoro-5-pyridazin-3-ylphenyl] -6-methoxymethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa -3-tia-1azanaftalen-2-il] amine
The compound obtained in Example 79- (1) (116 mg) was dissolved in dichloromethane (3 ml), and then TFA (1 ml) was added, followed by stirring at room temperature. After three hours, the reaction solution is
15 concentrated under reduced pressure. Chloroform and a solution of sodium bicarbonate were added to the residue, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography to obtain the title compound (48 mg).
ESI-MS; m / z 389 [M ++ 1].
20 Example 80
The following compound, as shown in the following Table 11, was synthesized according to Example 2 using the corresponding carboxylic acids.
[Table 11]

Example 80

Compound name: N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-trifluoromethyl4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -aza-naphthalen-8a-yl) -4-fluorophenyl] -5difluoromethylpyridin-2-carboxamide

ESI-MS m / z 505 [M ++ H]

25 Example 81
Synthesis of N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-8a-yl) -4-fluorophenyl] -5ethoxypyrazin-2-carboxamide image65
(1) Synthesis of 5-ethoxypyrazin-2-carboxylic acid
A 5 N solution of sodium hydroxide (2 ml) was added to a solution of methyl 5-chloropyrazine-2-carboxylate (150 mg) in ethanol (4 ml), and the mixture was stirred at room temperature for five hours. Ethyl acetate and water were added to the reaction solution, and the aqueous layer was separated. The aqueous layer was made acidic with acid.
5 concentrated hydrochloric. Brine and ethyl acetate were added to the mixture, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate. The organic layer was concentrated to obtain the title compound (135 mg).
1H-NMR (400 MHz, CDCl3) δ (ppm): 1.46 (t, J = 7.2 Hz, 3H), 4.51 (q, J = 7.2 Hz, 2H), 8.17 ( s, 1H), 8.96 (s, 1H).
(2) Synthesis of N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-8a -il) -4-fluorophenyl] -510 ethoxypyrazin-2-carboxamide
The title compound (30 mg) was obtained from the compound obtained in Example 1- (9) of preparation (30 mg), and the compound obtained in Example 81- (1) (16.9 mg) according to Example (2).
ESI-MS; m / z 432 [M ++ H]
1H-NMR (400 MHz, CDCl3) δ (ppm): 1.40-1.46 (m, 1H), 1.45 (t, J = 7.2 Hz, 3H), 2.07-2.18 (m, 1H), 2.64 (dd, J = 2.8,
15 8.0 Hz, 1H), 2.94 (ddd, J = 4.0, 7.6, 11.6 Hz, 1H), 3.02 (dd, J = 4.0, 12.0 Hz, 1H), 3.65-3.71 (m, 1H), 3.78 (d, J = 10.8 Hz, 1H), 4.04-4.11 (m, 2H), 4.49 (q , J = 7.2 Hz, 2H), 7.06 (dd, J = 8.8, 12.0 Hz, 1H), 7.32 (dd, J = 2.8, 7.2 Hz, 1H) , 7.99-8.03 (m, 1H), 8.11 (s, 1H), 8.98 (s, 1H), 9.47 (s, 1H).
Examples 82 to 87
The compounds of Examples 82 to 87 were synthesized according to Example 3 using the corresponding carboxylic acids, as shown in the following Table 12.
[Table 12-1] [Table 12-2]

Example 82

Chemical structure Compound name: N- [3 - ((8S *, 8aR *) - 2-amino-4,4a, 5,6,8,8ahexahydro-7-oxa-3-thia-1-azanaphthalen-8a- il) -4-fluorophenyl] -5-methoxypyrazin-2-carboxamide

1H-NMR (400MHz, CDCl3): δ (ppm): 1.44-1.47 (m, 1H), 2.08-2.18 (m, 1H), 2.64 (dd, J = 2.4, 12.0 Hz, 1H), 2.89-2.98 ( m, 1H), 3.03 (dd, J = 4.0, 12.0 Hz, 1H), 3.65-3.72 (m, 1H), 3.79 (d, J = 10.8 Hz, 1H), 4.02-4.12 (m, 5H), 7.07 (dd, J = 8.8, 12.0 Hz, 1H), 7.32 (dd, J = 2.8, 6.8 Hz, 1H), 8.02 (ddd, J = 2.8, 4.0, 8.8 Hz, 1H), 8.15 (d, J = 1.2 Hz, 1H), 9.01 (d, J = 1.6 Hz, 1H), 9.48 (sa, 1H)

ESI-MS m / z 418 [M ++ H]

Example 83

Chemical structure Compound name: N- [3 - ((8S *, 8aR *) - 2-amino-4,4a, 5,6,8,8ahexahydro-7-oxa-3-thia-1-azanaphthalen-8a- il) -4-fluorophenyl] -5-methoxypyridin-2-carboxamide

1H-NMR (400 MHz, CDCl3): 1.42-1.47 (m, 1H), 2.08-2.20 (m, 1H), 2.63 (dd, J = 2.8, 12.4 Hz, 1H), 2.91-2.97 (m, 1H) , 3.03 (dd, J = 4.0, 12.4 Hz, 1H), 3.65-3.72 (m, 1H), 3.78 (d, J = 10.8 Hz, 1H), 3.94 (s, 3H), 4.05-4.11 (m, 2H ), 7.06 (dd, J = 8.8, 12.0 Hz, 1H) 7.33 (dd, J = 2.8, 8.8 Hz, 2H), 8.04 (ddd, J = 2.8, 4.0, 8.8 Hz, 1H), 8.23 (d, J = 8.8 Hz, 1H), 8.27 (d, J = 2.8 Hz, 1H) 9.80 (sa, 1H)

ESI-MS m / z 417 [M ++ H]

Example 84

Chemical structure Compound name: N- [3 - ((8S *, 8aR *) - 2-amino-4,4a, 5,6,8,8ahexahydro-7-oxa-3-thia-1-azanaphthalen-8a- il) -4-fluorophenyl] -5fluoromethoxypyridin-2-carboxamide

1H-NMR (400 MHz, CDCl3): 1.44-1.48 (m, 1H), 2.09-2.19 (m, 1H), 2.65 (dd, J = 3.2, 12.4 Hz, 1H), 2.95-2.99 (m, 1H) , 3.04 (dd, J = 4.0, 12.0 Hz, 1H), 3.65-3.72 (m, 1H), 3.80 (d, J = 11.2 Hz, 1H), 4.04-4.13 (m, 2H), 5.81 (d, J = 50.0 Hz, 2H), 7.08 (dd, J = 8.8, 12.0 Hz, 1H) 7.35 (dd, J = 2.8, 6.8 Hz, 1H), 7.57 (ddd, J = 0.8, 2.8, 8.4 Hz, 1H), 8.05 (ddd, J = 2.8, 4.4, 8.8 Hz, 1H), 8.28 (dd, J = 0.4, 8.4 Hz, 1H), 8.42 (d, J = 2.8 Hz, 1H), 9.82 (sa, 1H)

ESI-MS m / z 435 [M ++ H]

Example 85

Chemical structure Compound name: N- [3 - ((8S *, 8aR *) - 2-amino-4,4a, 5,6,8,8ahexahydro-7-oxa-3-thia-1-azanaphthalen-8a- il) -4-fluorophenyl] -3-chloro-5trifluoromethylpyridin-2-carboxamide

1H-NMR (400 MHz, CDCl3): 1.45-1.48 (m, 1H), 2.07-2.18 (m, 1H), 2.66 (dd, J = 2.8, 12.4 Hz, 1H), 2.95-3.05 (m, 2H) , 3.65-3.72 (m, 1H), 3.78 (d, J = 11.2 Hz, 1H), 4.03-4.12 (m, 2H), 7.07-7.12 (m, 1H), 7.21 (dd, J = 2.4, 6.8 Hz , 1H), 8.13-8.18 (m, 2H), 8.79 (dd, J = 0.8, 4.0 Hz, 1H), 9.75 (sa, 1H)

ESI-MS m / z 489 [M ++ H]

[Table 12-3]

Example 86

Chemical structure Compound name: N- [3 - ((8S *, 8aR *) - 2-amino-4,4a, 5,6,8,8ahexahydro-7-oxa-3-thia-1-azanaphthalen-8a- il) -4-fluorophenyl] -5-methylpyridin-2carboxamide

1H-NMR (400 MHz, CDCl3): 1.44-1.47 (m, 1H), 2.12-2.15 (m, 1H), 2.65 (dd, J = 2.8, 12.4 Hz, 1H), 2.70 (s, 3H), 2.93 -2.97 (m, 1H), 3.03 (dd, J = 4.0, 12.4 Hz, 1H), 3.66-3.72 (m, 1H), 3.78 (d, J = 11.2 Hz, 1H), 4.05-4.12 (m, 2H ), 7.08 (dd, J = 8.8, 12.0 Hz, 1H) 7.36 (dd, J = 2.8, 6.8 Hz, 1H), 8.01-8.05 (m, 1H) 8.44 (s, 1H), 9.36 (d, J = 0.8 Hz, 1H), 9.61 (sa, 1 H)

ESI-MS m / z 402 [M ++ H]

Example 87

Chemical structure Compound name: N- [3 - ((8S *, 8aR *) - 2-amino-4,4a, 5,6,8,8ahexahydro-7-oxa-3-thia-1-azanaphthalen-8a- il) -4-fluorophenyl] -2-methylxazol-4carboxamide

1H-NMR (400 MHz, CDCl3): 1.45-1.48 (m, 1H), 2.11-2.14 (m, 1H), 2.53 (s, 3H), 2.63-2.67 (m, 1H), 2.95-3.05 (m, 2H), 3.65-3.71 (m, 1H), 3.81 (d, J = 11.6 Hz, 1H), 4.03-4.06 (m, 1H), 4.08-4.12 (m, 1H), 7.03-7.09 (m, 1H) , 7.30-7.32 (m, 1H), 7.93-7.97 (m, 1H), 8.17 (s, 1H), 8.71 (sa, 1H)

ESI-MS m / z 391 [M ++ H]

Example 88
The compound of Example 88 was synthesized according to Example 2 using the corresponding carboxylic acid and the corresponding aniline intermediate in the Preparation Examples, as shown in the following Table 13.
[Table 13]

Example 88

Chemical structure Compound name: N- [3 - ((8S, 8aS) -2-amino-5-fluoro-4,4a, 5,6-tetrahydro7-oxa-3-thia-1-azanaphthalen-8a-yl) -4-fluorophenyl] -5-methoxypyrazin-2-carboxamide

1H-NMR (400 MHz, CDCl3): 2.87-2.91 (m, 1H), 3.01-3.06 (m, 1H), 3.16 (dd, J = 2.8, 12.4 Hz, 1H), 3.53 (dt, J = 4.8, 10.4 Hz, 1H), 3.75 (dd, J = 2.0, 10.8 Hz, 1H), 4.07-4.10 (m, 4H), 4.26 (dd, J = 1.6, 10.8 Hz, 1H), 4.84-4.98 (m, 1H ), 7.10 (dd, J = 8.8, 12.0 Hz, 1H), 7.36 (dd, J = 2.4, 6.8 Hz, 1H), 7.97-8.01 (m, 1H), 8.15 (d, J = 1.2 Hz, 1H) , 9.01 (d, J = 1.2 Hz, 1H), 9.48 (sa, 1H)

ESI-MS m / z 436 [M ++ H]

Test Example 1
Quantification of A peptide in rat fetus brain neuron culture
5 (1) Rat Primary Neural Culture
Primary neuronal cultures were prepared from the cerebral cortex of Wistar 18-day embryonic rats (Charles River Japan, Yokohama, Japan). Specifically, embryos were aseptically removed from pregnant rats under ether anesthesia. The brain was isolated from the embryo and immersed in ice-cold L-15 medium (such as Catalog number 11415-064 from Invitrogen Corp., Carlsbad, CA, USA, or SIGMAL1518). The cerebral cortex 10 was collected from the isolated brain under stereomicroscope. The collected cerebral cortex fragments were treated enzymatically in an enzyme solution containing 0.25% trypsin (Catalog number 15050-065 from Invitrogen Corp., Carlsbad, CA, USA) and 0.01% DNase (Sigma D5025 , St. Louis, MO, USA) at 37 ° C for 30 minutes, to disperse the cells. Here, the enzymatic reaction was stopped by adding inactivated horse serum to the solution. The enzymatically treated solution was centrifuged at 1,500 rpm for 15 five minutes to remove the supernatant. To the resulting cell mass 5 to 10 ml of a medium was added. As the medium (Neurobasal / B27 / 2-ME), Neurobasal medium (Invitrogen Corp. Catalog number 21103049, Carlsbad, CA, USA) was used supplemented with 2% B27 supplement (Invitrogen Corp. Catalog number 17504- 044, Carlsbad, CA, USA), 25 M of 2-mercaptoethanol (2-ME, WAKO Catalog number 139-06861, Osaka, Japan) 0.5 mM L-glutamine (Invitrogen Corp. Catalog number. 25030-081, Carlsbad, CA, USA), and 20 antibiotics-antifungals (Catalog number of Invitrogen Corp. 15240-062, Carlsbad, CA, USA). However, for the test, the previous Neurobasal medium not supplemented with 2-ME (Neurobasal / B27) was used. The cells were dispersed again by lightly pipetting the cell mass to which the medium was added. The cell dispersion was filtered through a 40 µm nylon mesh (Cell Strainer, Catalog number 35-2340, Becton Dickinson Labware, Franklin Lakes, NJ, USA) to remove the remaining cell mass, and thus one was obtained
25 neuronal cell suspension.
The neuronal cell suspension was diluted with the medium and then plated in a volume of 100 µl / well at an initial cell density of 5 X 105 cells / cm 2 in a 96-well polystyrene culture plate previously coated with poly-L or D-lysine (Falcon Catalog number 35-3075, Becton Dickinson Labware, Franklin Lakes, NJ, USA coated with poly-L-lysine using the method shown below, or 96-well plate of 30 utensil for Poly-D-lysine cells in BIOCOAT ™ cellular environments, Catalog number 35-6461, Becton Dickinson Labware, Franklin Lakes, NJ, USA). The coating with poly-L-lysine was carried out according to the following. 100 µg / ml of a poly-L-lysine solution (SIGMA P2636, St. Louis, MO, USA) was prepared aseptically with a 0.15 M borate buffer (pH 8.5). 100 µg / well of the solution was added to the 96-well polystyrene culture plate and incubated at room temperature for one or more hours, or at 4 ° C overnight or more.
Then, the coated 96-well polystyrene culture plate was washed with sterile water four or more times, and then dried or rinsed with, for example, PBS or sterile medium, and used for cell placement in the license plate. Plaque cells were grown on the culture plate at 37 ° C in 5% CO2-95% air for one day. Then, the total amount of the medium was replaced by fresh Neurobasal / B27 / 2-ME medium, and then the cells were cultured for another three days.
40 (2) Addition of compound
The drug was added to the culture plate on Day 4 of culture as follows. The total amount of the medium was removed from the wells, and 180 µl / well of Neurobasal medium containing 2-ME and containing 2% B27 (Neurobasal / B27) was added. A solution of the test compound in dimethylsulfoxide (hereinafter abbreviated DMSO) was diluted with Neurobasal / B27 to a concentration 10 times higher than the final concentration. 20 were added
45 µl / well of the dilution a and mixed sufficiently with the medium. The final concentration of DMSO was 1% or less. Only DMSO was added to the control group.

(3)

Sampling

The cells were cultured for three days after the compound was added, and the total amount of the medium was collected. The resulting medium was used as an ELISA sample. The sample was not diluted for the ELISA measurement of Ax-42 and was diluted up to 5 times with a diluent supplied with an ELISA kit for the measurement of ELISA of Ax-40.

(4)

Cellular Survival Assessment

5 Cell survival was assessed by an MTT assay according to the following procedure. After collecting the medium, 100 µl / well of a previously heated medium was added to the wells. In addition, 8 µl / well of an 8 mg / ml solution of MTT (SIGMA M2128, St. Louis, MO, USA) in D-PBS (-) (Dulbecco phosphate buffered saline solution, were added to the wells, SIGMA D8537, St. Louis, MO, USA). The 96-well polystyrene culture plate was incubated in an incubator at 37 ° C in 5% CO2-95% air for 20
10 minutes. 100 µl / well of an MTT lysis buffer was added, and the formazan MTT crystals were sufficiently dissolved in the buffer in the incubator at 37 ° C in 5% CO2-95% air. Then, the absorbance at 550 nm in each well was measured. The MTT lysis buffer was prepared as follows. 100 g of SDS (sodium dodecyl sulfate (sodium lauryl sulfate), WAKO 191-07145, Osaka, Japan) was dissolved in a mixed solution of 250 ml of N, N-dimethylformamide (WAKO 045-02916, Osaka, Japan) with 250 ml of distilled water. They were added
In addition to the solution 350 µl of each of concentrated hydrochloric acid and acetic acid, to allow the solution to have a final pH of about 4.7.
With the measurement, wells that do not have cells in the plates and that only contain the medium and MTT solution were established as bottom (bkg). The measured values were applied respectively to the following formula, which includes the subtraction of their bkg values. Thus, the proportion against the control group (untreated group
20 with the drug, CTRL) (% of CTRL) was calculated to compare and evaluate cell survival activities.
% of CTRL = (A550_sample -A550_bkg) / (A550_CTRL - A550_bkg) x 100
(A550_sample: absorbance at 550 nm of the sample well, A550_bkg: absorbance at 550 nm of bottom well, A550_CTRL: absorbance at 550 nm of well of the control group)
(5) ELISA of A
For A ELISA, human  amyloid (42) / Wako rat (# 290-62601) ELISA kit and humana human humana amyloid (40) / Wako rat (# 294-62501) ELISA kit from Wako was used Pure Chemical Industries, Ltd. The ELISA of A was carried out according to the protocols recommended by the manufacturers (methods described in the attached documents). However, the A calibration curve was created using rat beta-amyloid peptide 1-42 and rat betaamiloid peptide 1-40 (Calbiochem, # 171596 [A42], # 171593 [A40] ). The results are shown in Table 14 in
30 terms of the value of IC50 (M) to decrease the concentration of A42 in the medium.
[Table 14]

Test compound

of IC50 of the reducing effect production of A (42 (M) of the compound Test of IC50 of the reducing effect of production of A42 (M)

one

image66 0.0017 image67 33 image68 0.0011

2

image69 0.002 image70 3. 4 image71 0.002

3

image72 0.001 image73 35 image74 0.0021

4

image75 0.011 image76 36 image77 0.0005

5

image78 0.058 image79 37 image80 0.002

6

image81 0.0012 image82 38 image83 0.003

7

image84 0.0007 image85 39 image86 0.001

8

image87 0.0016 image88 40 image89 0.002

9

image90 0.0006 image91 41 image92 0.002

Test compound

of IC50 of the production reducing effect of A42 (M) of Test compound IC50 of the production reducing effect of A42 (M)

10

image93 0.001 image94 42 0.0009

eleven

image95 0.0007 image96 43 0.0017

12

image97 0.0011 image98 44 0.0007

13

image99 0.001 image100 45 0.002

14

image101 0.0008 image102 46 0.001

fifteen

image103 0.0004 image104 47 0.004

16

image105 0.0011 image106 48 0.002

17

image107 0.004 image108 49 0.002

18

image109 0.007 image110 50 0.002

19

image111 0.002 image112 51 0.006

twenty

image113 0.009 image114 52 0.002

twenty-one

image115 0.01 image116 53 0.0056

22

image117 0.004 image118 54 0.002

2. 3

image119 0.012 image120 55 0.0014

24

image121 0.009 image122 56 0.003

25

image123 0.014 image124 57 0.002

26

image125 0.003 image126 58 0.004

27

image127 0.008 image128 59 0.087

28

image129 0.0014 image130 60 0.032

29

image131 0.003 image132 61 0.319

30

image133 0.006 image134 64 0.014

31

image135 0.0019 image136 65 0.37

32

image137 0.003 image138 66 0.263

As is clear from the results in Table 14, it was shown that the compound of the present invention has a reducing effect on the production of A42. Industrial applicability The compound of the general formula (I) or its pharmaceutically acceptable salt, or solvate thereof, according to the
The present invention has a reducing effect on the production of A42. Thus, the present invention can particularly provide a prophylactic or therapeutic agent for a neurodegenerative disease caused by A, such as Alzheimer's dementia or Down syndrome.

Claims (14)

1. A compound represented by the formula (I): image 1 or a pharmaceutically acceptable salt thereof, or a solvate thereof, in which 5 Ring A is a C6-14 aryl group that may have 1 to 3 substituents selected from the Substituent Group , a 5- to 6-membered heteroaryl group that may have 1 to 3 substituents selected from the Substituent Group  or a benzo heterocyclic group - condensate of 9 to 10 members that may have 1 to 3 substituents selected from the Substituent Group , L is a single bond, an oxygen atom, -NRLCO- (in which RL is a hydrogen atom or a group C1-6 alkyl which may have 1 to 3 substituents selected from the Substituent Group ), a -NRLCO C1-6 alkyl group (wherein RL is a hydrogen atom or a C1-6 alkyl group which may have 1 to 3 substituents selected from the Substituent Group ), -NRLSO2- (in which RL is a hydrogen atom or a C1-6 alkyl group which may have 1 to 3 substituents selected from the Substituent Group ), a C1 alkylene group -6 which may have 1 to 3 substituents selected from the Substituent Group , an alkenyl group 15 of C2-6 which may have 1 to 3 substituents selected from the Substituent Group , or a C2-6 alkynylene group which may have 1 to 3 substituents selected from the Substituent Group , Ring B is a C3-8 cycloalkyl group that may have 1 to 3 substituents selected from the Substituent Group , an aryl group of C6-14 that may have 1 to 3 substituents selected from the Substituent Group , or a heterocyclic group of 5 10 members who can have 1 to 3 substituents selected from the Group 20 Substituent , X is a single bond or a C1-3 alkylene group which may have 1 to 3 substituents selected from the Substituent Group , Y is a C1-3 alkylene group which may have 1 to 3 substituents selected from the Substituent Group  or a C2-3 alkenylene group which may have 1 to 3 substituents selected from the Substituent Group , Z is an oxygen atom, a sulfur atom, a sulfoxide, a sulfone or -NRM- (in which RM is a hydrogen atom, a C1-6 alkyl group that may have 1 to 3 substituents selected from the Group Substituent , a C3-8 cycloalkyl group that may have 1 to 3 substituents selected from the Substituent Group , a C1-6 alkylcarbonyl group that may have 1 to 3 substituents selected from the Substituent Group , a C6-14 aryl group -carbonyl which may have 1 to 3 substituents selected from the Substituent Group , an alkyl group C1-6-sulfonyl which may have 1 to 3 substituents selected from the Substituent Group , an aryl C6-14 sulfonyl group which may have 1 to 3 substituents selected from the Substituent Group , an aryl group of C6-14 which may have 1 to 3 substituents selected from the Substituent Group , or a 5-10 membered heterocyclic group that may have 1 to 3 substituents selected from the Substituent Group ), R1 and R2 are each independently a hydrogen atom, a C1-6 alkyl group that may have 1 to 35 3 substituents selected from the Substituent Group , a C1-6 alkylcarbonyl group which may have 1 to 3 substituents selected from the Substituent Group , an aryl C6-14-carbonyl group which may have 1 to 3 substituents selected from the Substituent Group  , a C1-6 alkyl sulfonyl group which may have 1 to 3 substituents selected from the Substituent Group , an aryl C6-14-sulfonyl group which may have 1 to 3 substituents selected from the Substituent Group , a carbocyclic group of C3-8 which can have 1 to 3 40 substituents selected from the Substituent Group , or a 5-10 membered heterocyclic group that may have 1 to 3 substituents selected from the Substituent Group , and R3, R4, R5 and R6 are independently a hydrogen atom, a halogen atom, a hydroxy group, a C1-6 alkyl group which may have 1 to 3 substituents selected from the Substituent Group , a C1-6 alkoxy group which may have 1 to 3 substituents selected from the Substituent Group , a carbocyclic group R4 and R6, together, can form a ring represented by the formula (II); image2 5 in which Y, Z, R5 and R3 are as defined above, and Q is an oxygen atom, a methylene group or an ethylene group [Substituent Group : a hydrogen atom, a halogen atom, a hydroxy group, a nitro group, a C1-6-thio alkyl group, a C6-14 aryl group, a C6-14-oxycarbonyl aryl group, a C6-14-aryl carbonyl group, a cyano group, a C3-8 cycloalkoxy group, a C3-8 cycloalkyl group, a C3-8-thio cycloalkyl group, a sulfonylamino group (in which the sulfonylamino group may be substituted with 1 to 2 C1-6 alkyl groups), a C2-6 alkenyl group which may have 1 to 2 substituents selected from the Substituent Group , a C2-6 alkynyl group which may have 1 to 2 substituents selected from the Group Substituent , a carbamoyl group which may be substituted with 1 to 2 C1-6 alkyl groups, a C1-6 alkoxy group which may have 1 to 3 substituents selected from the Substituent Group , a C1-6 alkyl group which may have 1 to 3 15 substituents selected from the Substituent Group , and a 5-10 membered heterocyclic group that may have 1 to 3 substituents selected from the Substituent Group , Substituent Group : a halogen atom, a cyano group, a hydroxy group and a C1-6 alkoxy group (in which the alkoxy group may be substituted with a phenyl group which may be substituted with 1 to 3 substituents selected from a hydrogen atom, a halogen atom, a hydroxy group and a nitro group)]. A compound represented by the formula (I): image3 or a pharmaceutically acceptable salt thereof, or a solvate thereof according to reinvidication 1, in which Ring A is a C6-14 aryl group that may have 1 to 3 substituents selected from the Substituent Group , a 5- to 6-membered heteroaryl group that may have 1 to 3 substituents selected from the Group 25 Substituent , or a benzo-condensed heterocyclic group of 9 to 10 members which may have 1 to 3 substituents selected from the Substituent Group , L is a single bond, an oxygen atom, -NRLCO- (where RL is a hydrogen atom or a C1-6 alkyl group which may have 1 to 3 substituents selected from the Substituent Group ), -NRLSO2- ( wherein RL is a hydrogen atom or a C1-6 alkyl group that may have 1 to 3 substituents selected 30 of the Substituent Group ), a C1-6 alkylene group which may have 1 to 3 substituents selected from the Substituent Group , a C2-6 alkenylene group which may have 1 to 3 substituents selected from the Substituent Group , or a group C2-6 alkynylene which may have 1 to 3 substituents selected from the Substituent Group , Ring B is a C3-8 cycloalkyl group that may have 1 to 3 substituents selected from the Group 35 Substituent , a C6-14 aryl group that may have 1 to 3 substituents selected from the Substituent Group , or a 5 to 10 membered heterocyclic group that may have 1 to 3 substituents selected from the Substituent Group , Y is a C1-3 alkylene group which may have 1 to 3 substituents selected from the Substituent Group , or a C2-3 alkenylene group which may have 1 to 3 substituents selected from the Substituent Group , 5 Z is an oxygen atom, a sulfur atom, a sulfoxide, a sulfone or -NRM- (in which RM is a hydrogen atom, a C1-6 alkyl group that may have 1 to 3 substituents selected from the Group Substituent , a C3-8 cycloalkyl group that may have 1 to 3 substituents selected from the Substituent Group , a C1-6 alkylcarbonyl group that may have 1 to 3 substituents selected from the Substituent Group , a C6-14 aryl group -carbonyl which may have 1 to 3 substituents selected from the Substituent Group , an alkyl group C1-6-sulfonyl which may have 1 to 3 substituents selected from the Substituent Group , an aryl C6-14 sulfonyl group which may have 1 to 3 substituents selected from the Substituent Group , an aryl group of C6-14 which may have 1 to 3 substituents selected from the Substituent Group  or a 5-10 membered heterocyclic group that may have 1 to 3 substituents selected from the Substituent Group ), R1 and R2 are each independently a hydrogen atom, a C1-6 alkyl group that may have 1 to 15 3 substituents selected from the Substituent Group , a C1-6 alkylcarbonyl group which may have 1 to 3 substituents selected from the Substituent Group , an aryl C6-14-carbonyl group which may have 1 to 3 substituents selected from the Substituent Group  , a C1-6 alkyl sulfonyl group which may have 1 to 3 substituents selected from the Substituent Group , an aryl C6-14-sulfonyl group which may have 1 to 3 substituents selected from the Substituent Group , a carbocyclic group of C3-8 which can have 1 to 3 20 substituents selected from the Substituent Group , or a 5-10 membered heterocyclic group that may have 1 to 3 substituents selected from the Substituent Group , and R3, R4, R5 and R6 are independently a hydrogen atom, a halogen atom, a hydroxy group, a C1-6 alkyl group which may have 1 to 3 substituents selected from the Substituent Group , a C1-6 alkoxy group which may have 1 to 3 substituents selected from the Substituent Group , a carbocyclic group 25 of 3 to 10 members that may have 1 to 3 substituents selected from the Substituent Group , or a heterocyclic group of 5 to 10 members that may have 1 to 3 substituents selected from the Substituent Group o, or R4 and R6, together, can form a ring represented by formula (II): image4 wherein Y, Z, R5 and R3 are as defined above, and Q is an oxygen atom, a methylene group or an ethylene group [Substituent Group : a hydrogen atom, a halogen atom, a hydroxy group, a nitro group, a group C1-6-thio alkyl, a C6-14 aryl group, a C6-14-oxycarbonyl aryl group, a C6-14-aryl carbonyl group, a group cyano, a C3-8 cycloalkoxy group, a C3-8 cycloalkyl group, a C3-8-thio cycloalkyl group, a group sulfonylamino (in which the sulfonylamino group may be substituted with 1 to 2 C1-6 alkyl groups), a C2-6 alkenyl group which may have 1 to 2 substituents selected from the group of substituents , a group C2-6 alkynyl which may have 1 to 2 substituents selected from the group of substituents , a group carbamoyl which may be substituted with 1 to 2 C1-6 alkyl groups, a C1-6 alkoxy group which may have 1 to 3 substituents selected from the Substituent Group , a C1-6 alkyl group that may have 1 to 3 substituents selected from the Substituent Group , and a 5-10 membered heterocyclic group that may have 1 to 3 substituents selected from the Substituent Group , Substituent Group : a halogen atom, a cyano group, a hydroxy group and a C1-6 alkoxy group]. 3. The compound represented by the formula (I): or a pharmaceutically acceptable salt thereof, or a solvate thereof according to reinvidication 1, in which image5 Ring A is a C6-14 aryl group that may have 1 to 3 substituents selected from the Substituent Group , a 5- to 6-membered heteroaryl group that may have 1 to 3 substituents selected from the Substituent Group , or a benzo heterocyclic group - condensate of 9 to 10 members that may have 1 to 3 substituents selected from the Substituent Group , L is a single bond, an oxygen atom, -NRLCO- (where RL is a hydrogen atom or a C1-6 alkyl group which may have 1 to 3 substituents selected from the Substituent Group ), -NRLSO2- ( wherein RL is a hydrogen atom or a C1-6 alkyl group that may have 1 to 3 substituents selected from the Substituent Group ), a C1-6 alkylene group that may have 1 to 3 substituents selected from the Substituent Group  , a C2-6 alkenylene group which may have 1 to 3 substituents selected from the Substituent Group , or a C2-6 alkynylene group which may have 1 to 3 substituents selected from the Substituent Group , Ring B is a C3-8 cycloalkyl group that may have 1 to 3 substituents selected from the Substituent Group , an aryl group of C6-14 that may have 1 to 3 substituents selected from the Substituent Group , or a heterocyclic group of 5 10 members who can have 1 to 3 substituents selected from the Substituent Group , X is a single bond or a C1-3 alkylene group which may have 1 to 3 substituents selected from the Substituent Group , Y is a C1-3 alkylene group which may have 1 to 3 substituents selected from the Substituent Group , or a C2-3 alkenylene group which may have 1 to 3 substituents selected from the Substituent Group , Z is an oxygen atom, a sulfur atom, a sulfoxide, a sulfone or -NRM- (in which RM is a hydrogen atom, a C1-6 alkyl group that may have 1 to 3 substituents selected from the Substituent Group , a C3-8 cycloalkyl group that may have 1 to 3 substituents selected from the Substituent Group , a C1-6 alkylcarbonyl group that may have 1 to 3 substituents selected from the Substituent Group , an aryl group C6-14- carbonyl which may have 1 to 3 substituents selected from the Substituent Group , a C1-6 alkyl sulfonyl group that may have 1 to 3 substituents selected from the Substituent Group , an aryl C6-14 sulfonyl group which may have 1 to 3 substituents selected from the Substituent Group , a C6-14 aryl group that may have 1 to 3 substituents selected from the Substituent Group , or a 5-10 membered heterocyclic group that may have 1 to 3 substituents selected from the Substituent Group ), R1 and R2 are each independently a hydrogen atom, a C1-6 alkyl group that may have 1 to 3 substituents selected from the Substituent Group , a C1-6 alkylcarbonyl group that may have 1 to 3 substituents selected from the Group Substituent , a C6-14-aryl carbonyl group which may have 1 to 3 substituents selected from the Substituent Group , a C1-6 alkyl sulfonyl group which may have 1 to 3 substituents selected from the Substituent Group , a C6-aryl group 14-sulfonyl which may have 1 to 3 substituents selected from the Substituent Group , a C3-8 carbocyclic group that may have 1 to 3 substituents selected from the Substituent Group , or a 5 to 10 membered heterocyclic group that may have 1 to 3 substituents selected from the Substituent Group , and R3, R4, R5 and R6 are independently a hydrogen atom, a halogen atom, a hydroxy group, a C1-6 alkyl group which may have 1 to 3 substituents selected from the Substituent Group , a C1-6 alkoxy group which may have 1 to 3 substituents selected from the Substituent Group , a carbocyclic group of 3 to 10 members that may have 1 to 3 substituents selected from the Substituent Group , or a heterocyclic group of 5 to 10 members that may have 1 to 3 substituents selected from the Substituent Group  [Substituent Group : a hydrogen atom, a halogen atom, a hydroxy group, a nitro group, a C1-6-thio alkyl group, a C6-14 aryl group, a C6-14-oxycarbonyl aryl group, a C6-14-aryl-carbonyl group, a cyano group, a C3-8 cycloalkoxy group, a C3-8 cycloalkyl group, a C3-8-thio cycloalkyl group, a sulfonylamino group (in which the sulfonylamino group may be substituted with 1 to 2 C1-6 alkyl groups), a C2-6 alkenyl group that may have 1 to 2 substituents selected from the Substituent Group , a C2-6 alkynyl group that may have 1 to 2 substituents selected from the Substituent Group , a carbamoyl group that may be substituted with 1 to 2 C1-6 alkyl groups, a C1-6 alkoxy group that may have 1 to 3 substituents selected from the Substituent Group , a C1-6 alkyl group that may have 1 to 3 substituents selected from the Substituent Group , and a 5-10 membered heterocyclic group that can 1 to 3 substituents selected from the Substituent Group , Substituent Group : a halogen atom, a cyano group, a hydroxy group and a C1-6 alkoxy group].

Four.

The compound or pharmaceutically acceptable salt thereof, or solvate thereof according to any one of claims 1 to 3, wherein X is a methylene group which may have 1 to 2 substituents selected from the Substituent Group .

5.

The compound or pharmaceutically acceptable salt thereof, or solvate thereof according to any one of claims 1 to 4, wherein Z is an oxygen atom and Y is a C1-3 alkylene group that may have 1 to 3 substituents selected of the Substituent Group .

6.

The compound or pharmaceutically acceptable salt thereof, or solvate thereof according to any one of claims 1 to 4, wherein Z is an oxygen atom and Y is a C2-3 alkenylene group which may have 1 to 3 substituents selected. of the Substituent Group .

7.

The compound or pharmaceutically acceptable salt thereof, or solvate thereof according to any one of claims 1 to 4, wherein Z is a sulfur atom or a sulfone and Y is a C1-3 alkylene group which may have 1 to 3 substituents selected from the Substituent Group .

8.

The compound or pharmaceutically acceptable salt thereof, or solvate thereof according to any one of claims 1 to 7, wherein L is NRLCO- (wherein RL is a hydrogen atom or a C1-6 alkyl group which can have 1 to 3 substituents selected from the Substituent Group ).

9.

The compound or pharmaceutically acceptable salt thereof, or solvate thereof according to any one of claims 1 to 8, wherein the substituents selected from the Substituent Group  is a hydrogen atom, a halogen atom, a C1- alkoxy group 6 which may have 1 to 3 substituents selected from the Substituent Group , or a C1-6 alkyl group which may have 1 to 3 substituents selected from the Substituent Group .

10.

The compound or a pharmaceutically acceptable salt thereof, or a solvate thereof according to claim 1, wherein the compound is selected from the following compounds:

1) N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-4,4a, 5,6,8,8a-hexahydro-7- oxa-3-thia-1-azanaphthalen-8ail) -4-fluorophenyl] -5-cyanopyridin-2-carboxamide, 2) N- [3 - ((8S *, 8aR *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-8a-yl) -4-fluorophenyl] -5fluoromethoxypyrazin-2-carboxamide, 3) N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-8a-yl) -4-fluorophenyl] -5difluoromethoxypyrazin-2-carboxamide, 4) N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-8a-yl) -4-trifluoromethoxyphenyl] -5cianopyridin-2-carboxamide, 5) N- [3 - ((8S *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-8a-yl) -4-trifluoromethoxyphenyl] -5chloropyridin-2-carboxamide, 6) N- [3 - ((4aR *, 6S *, 8aS *) - 2-amino-6-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4fluorophenyl] -5-chloropyridin-2-carboxamide, 7) N- [3 - ((4aR *, 6S *, 8aS *) - 2-amino-6-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4fluorophenyl] -5-cyanopyridin-2-carboxamide, 8) N- [3 - ((4aR *, 6S *, 8aS *) - 2-amino-6-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4fluorophenyl] -5-trifluoromethylpyridin-2-carboxamide, 9) N- [3 - ((4aR *, 6S *, 8aS *) - 2-amino-6-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-il) -4fluorophenyl] -5-difluoromethoxypyrazin-2-carboxamide, 11) N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-methoxymethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4fluorophenyl] -5-cyanopyridin-2-carboxamide, 12) N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-methoxymethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-il) -4fluorophenyl] -5-difluoromethylpyrazin-2-carboxamide, 13) N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-methoxymethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4fluorophenyl] -5-chloropyridin-2-carboxamide, 14) N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-methoxymethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-il) -4fluorophenyl] -5-fluoromethoxypyrazin-2-carboxamide, 15) N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-methoxymethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-il) -4fluorophenyl] -5-difluoromethoxypyrazin-2-carboxamide, 16) N- [3 - ((4aS, 5S, 8aS) -2-amino-5-fluoro-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen- 8a-yl-4-fluorophenyl] 5-cyanopyridin-2-carboxamide, 17) N- [3 - ((4aS, 5S, 8aS) -2-amino-5-fluoro-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen- 8a-yl) -4fluorophenyl] -5-difluoromethylpyrazin-2-carboxamide, 18) N- [3 - ((4aS, 5S, 8aS) -2-amino-5-fluoro-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen- 8a-yl) -4fluorophenyl] -5-chloropyridin-2-carboxamide, 19) N- [3 - ((4aS, 5S, 8aS) -2-amino-5-fluoro-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen- 8a-yl) -4fluorophenyl] -5-trifluoromethylpyridin-2-carboxamide, 20) N- [3 - ((4aS, 5S, 8aS) -2-amino-5-fluoro-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen- 8a-yl) -4fluorophenyl] -5-difluoromethoxypyridin-2-carboxamide, 21) N- [3 - ((4aS, 5S, 8aS) -2-amino-5-fluoro-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen- 8a-yl) -4fluorophenyl] -5-fluoromethoxypyrazin-2-carboxamide, 22) N- [3 - ((4aS, 5S, 8aS) -2-amino-5-fluoro-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen- 8a-yl) -4fluorophenyl] -5-difluoromethoxypyrazin-2-carboxamide, 23) N- [3 - ((4aR *, 5S *, 8aS *) - 2-amino-5-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4fluorophenyl] -5-chloropyridin-2-carboxamide, 24) N- [3 - ((4aR *, 5S * .8aS *) - 2-amino-5-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4fluorophenyl] -5-cyanopyridin-2-carboxamide, 25) N- [3 - ((4aR *, 5S *, 8aS *) - 2-amino-5-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-il) -4fluorophenyl] -5-difluoromethoxypyrazin-2-carboxamide, 26) N- [3 - ((4aR *, 5R *, 8aS *) - 2-amino-5-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4fluorophenyl] -5-chloropyridin-2-carboxamide, 27) N- [3 - ((4aR *, 5R *, 8aS *) - 2-amino-5-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4fluorophenyl] -5-cyanopyridin-2-carboxamide, 28) N- [3 - ((4aR *, 5R *, 8aS *) - 2-amino-5-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-il) -4fluorophenyl] -5-difluoromethoxypyrazin-2-carboxamide, 29) N- [3 - ((4aR *, 5R *, 8aS *) - 2-amino-5-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-il) -4fluorophenyl] -5-difluoromethylpyrazin-2-carboxamide, 30) N- [3 - ((4aS *, 5R *, 8aS *) - 2-amino-5-methoxy-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4fluorophenyl] -5-cyanopyridin-2-carboxamide, 31) N- [3 - ((2R *, 4aR *, 8aS *) - 2-amino-4-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4fluorophenyl] -5-cyanopyridin-2-carboxamide, 32) N- [3 - ((2R *, 4aR *, 8aS *) - 2-amino-4-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-il) -4fluorophenyl] -5-difluoromethylpyrazin-2-carboxamide, 34) N- [3 - ((4aR, 6R, 8aS) -2-amino-6-hydroxymethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen- 8a-yl) -4fluorophenyl] -5-cyanopyridin-2-carboxamide, 35) N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-trifluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4fluorophenyl] -5-cyanopyridin-2-carboxamide, 36) N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-trifluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-il) -4fluorophenyl] -5-difluoromethoxypyrazin-2-carboxamide, 37) N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-trifluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4fluorophenyl] -5-fluoropyridin-2-carboxamide, 38) N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-trifluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4fluorophenyl] -pyridin-2-carboxamide, 39) N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-trifluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-il) -4fluorophenyl] -5-fluoromethoxypyrazin-2-carboxamide, 40) N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-trifluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-il) -4fluorophenyl] -pyrimidin-4-carboxamide, 41) N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-trifluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4fluorophenyl] -3,5-difluoropyridin-2-carboxamide, 42) N- (3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-trifluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4fluorophenyl] -5-difluoromethoxypyridin-2-carboxamide, 43) N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-trifluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-il) -4fluorophenyl] -5-difluoromethylpyrazin-2-carboxamide, 44) N- [3 - ((4aR, 6R, 8aS) -2-amino-6-fluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen- 8a-yl) -4fluorophenyl] -5-cyanopyridin-2-carboxamide, 45) N- [3 - ((4aR, 6R, 8aS) -2-amino-6-fluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen- 8a-yl) -4fluorophenyl] -5-chloropyridin-2-carboxamide, 46) N- [3 - ((4aR, 6R, 8aS) -2-amino-6-fluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen- 8a-yl) -4fluorophenyl] -5-trifluoromethylpyridin-2-carboxamide, 47) N- [3 - ((4aR, 6R, 8aS) -2-amino-6-fluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen- 8a-yl) -4fluorophenyl] -5-fluoromethoxypyrazin-2-carboxamide, 48) N- [3 - ((4aR, 6R, 8aS) -2-amino-6-fluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen- 8a-yl) -4fluorophenyl] -5-difluoromethylpyrazin-2-carboxamide, 49) N- [3 - ((4aR *, 8aS *) 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-8a-yl) - 4-fluorophenyl] -5chloropyridin-2-carboxamide, 50) N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-8a-yl) -4-fluorophenyl] -5bromopyridin-2-carboxamide, 51) N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-8a-yl) -4-fluorophenyl] -3,5difluoropyridin-2-carboxamide, 52) N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-8a-yl) -4-fluorophenyl] -3,5-dichloropyridin-2-carboxamide, 53) N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-8a-yl) -4-fluorophenyl] -5fluoropyridin-2-carboxamide, 54) N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-8a-yl) -4-fluorophenyl] -3,5-dibromopyridin-2-carboxamide, 55) N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-8a-yl) -4-fluorophenyl] -5trifluoromethylpyridin-2-carboxamide, 57) N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-8a-yl) -4-fluorophenyl] -5difluoromethylpyrazin-2-carboxamide, 58) N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-8a-yl) -4 -fluorophenyl] -5difluoromethoxypyridin-2-carboxamide, 59) (±) - (4aR *, 6R *, 8aS *) - 8a- [2-fluoro-5- (2-fluoropyridin-3-yl) phenyl] -6-trifluoromethyl-4,4a, 5,6, 8,8a-hexahydro-7-oxa3-thia-1-azanaphthalen-2-ylamine, 60) (4aR, 6R, 8aS) -8a- [2-fluoro-5- (2-fluoropyridin-3-yl) phenyl] -6-fluoromethyl-4,4a, 5,6,8,8a-hexahydro-7 -oxa-3-tia-1azanaftalen-2-ylamine, 61) (±) - (4aR *, 8aS *) - 8a- [2-fluoro-5- (2-fluoropyridin-3-yl) phenyl] -4,4a, 5,6,8,8a-hexahydro-7 -oxa-3-thia-1-azanaphthalen2-ylamine, 62) (±) - (4aR *, 8aS *) - 8a- (2-fluoro-5-pyrimidin-5-ylphenyl) -4,4a, 5,6,8,8a-hexahydro-7-oxa-3- thia-1-azanaphthalen-2-amine, 63) (±) - (4aR *, 8aS *) - 8a- [5- (5-chloropyridin-3-yl) -2-fluorophenyl] -4,4a, 5,6,8,8a-hexahydro-7- oxa-3-thia-1-azanaphthalen2-ylamine, 64) N- [5 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-8a-yl) thiophene-3-yl] -5cianopyridin-2-carboxamide, 65) (±) - (4aR *, 8aR *) - 8a- [4- (2-fluoropyridin-3-yl) -thiophene-2-yl] -4,4a, 5,6,8,8a-hexahydro- 7-oxa-3-thia-1-azanaphthalen-2-amine, 66) (4aR, 6R, 8aS) -8a- [2-fluoro-5- (2-fluoropyridin-3-yl) phenyl] -6-benzyloxymethyl-4,4a, 5,6,8,8a-hexahydro-7 -oxa-3-thia1-azanaphthalen-2-ylamine, 67) (±) -N- [7 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen- 8a-yl) -2,2difluorobenzo [1,3] dioxol-5-yl] -5-cyanopyridin-2-carboxamide, 68) N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-8a-yl) -4-fluorophenyl] -5- (2-methoxyethoxy) -pyrazin-2-carboxamide, 69) N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-8a-yl) -4-fluorophenyl] -2methylthiazol-4-carboxamide, 70) N- [3 - ((4aR *, 5R *, 8aS *) - 2-amino-5-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4fluorophenyl] -2,5-dimethylfuran-3-carboxamide, 71) N- [3 - ((4aR *, 5R *, 8aS *) - 2-amino-5-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4fluorophenyl] -4-methyl- [1,2,3] thiadiazol-5-carboxamide, 72) N- [3 - ((4aR *, 5R *, 8aS *) - 2-amino-5-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4fluorophenyl] -3-piperidin-1-ylpropionamide, and 73) N- [3 - ((4aR *, 5R *, 8aS *) - 2-amino-5-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaftalen-8a-yl) -4fluorophenyl] -2-methylxazol-4-carboxamide, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

eleven.

A pharmaceutical composition comprising as active ingredient the compound or pharmaceutically acceptable salt thereof, or solvate thereof according to any one of claims 1 to 10;

12.

The pharmaceutical composition according to claim 11, to inhibit the production of -amyloid protein;

13.

The pharmaceutical composition according to claim 11, to inhibit the cleavage enzyme 1 of the beta-site -amyloid precursor protein (BACE1);

14.

The pharmaceutical composition according to any one of claims 11 to 13, for treating a neurodegenerative disease.

fifteen.

The pharmaceutical composition according to claim 14, wherein the neurodegenerative disease is Alzheimer's dementia or Down syndrome.